Method for directed intranasal administration of a composition

ABSTRACT

Methods, kits, apparatus, and compositions for inhibiting a cerebral neurovascular disorder, a muscular headache, or cerebral inflammation in a human patient are provided. The methods comprise intranasally administering to the patient a pharmaceutical composition comprising a local anesthetic, and preferably a long-acting local anesthetic ingredient. A composition useful for practicing the methods of the invention is described which comprises at least one local anesthetic in a pharmaceutically acceptable carrier, wherein the composition is formulated for intranasal delivery. Cerebral neurovascular disorders include migraine and cluster headache. Muscular headaches include tension headaches and muscle contraction headaches. A kit comprising the composition and an intranasal applicator and a method of systemically delivering a pharmaceutically active agent to an animal are also included in the invention. Apparatus for directed intranasal administration of the compositions of the invention and for performing the methods of the invention are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of pending U.S. application Ser. No.10/218,138, filed Aug. 12, 2002. application Ser. No. 10/218,138 is acontinuation-in-part of three prior applications, namely, U.S.application Ser. No. 09/737,302, filed Dec. 15, 2000, now abandoned;U.S. application Ser. No. 09/492,946, filed Jan. 27, 2000, now U.S. Pat.No. 6,491,940; and U.S. application Ser. No. 09/118,615, filed Jul. 17,1998, now U.S. Pat. No. 6,432,986. application Ser. No. 09/737,302 is acontinuation-in-part of application Ser. No. 09/118,615 and is alsoentitled to priority pursuant to 35 U.S.C. §119(e) to U.S. ProvisionalApplication No. 60/170,817, filed Dec. 15, 1999. Application Ser. No.09/492,946 is entitled to priority pursuant to 35 U.S.C. 119(e) to U.S.Provisional Application No. 60/117,398, filed Jan. 27, 1999. ApplicationSer. No. 09/118,615 is entitled pursuant to 35 U.S.C. §119(e) to U.S.Provisional Application No. 60/090,110, filed Jul. 21, 1997; U.S.Provisional Application No. 60/072,845, filed Jan. 28, 1998; and to U.S.Provisional Application No. 60/084,559, filed May 6, 1998.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

REFERENCE TO A MICROFICHE APPENDIX

Not applicable.

BACKGROUND OF THE INVENTION

This invention relates to compositions, kits, methods, and apparatus forinhibiting muscular headaches and cerebral neurovascular disordersincluding, but not limited to, neurovascular headaches, migraines,cluster headaches, tinnitus, cerebrovascular spasm, ischemic disorders,seizures, central neuraxial motor, sensory, and cognitive deficits,degenerative, traumatic, or infectious lesions of the central nervoussystem, and cephalic inflammation including, but not limited to,meningeal inflammation, intracranial inflammation, extracranialinflammation. The invention also relates to apparatus and methods fordirecting intranasal administration of a composition to a selectedportion of the nasal cavity, such as the superior portion or thedorsonasal portion.

Headache is a common symptom of numerous diseases and disordersincluding, but not limited to, migraine, muscle tension, systemic orintracranial infection, intracranial tumor, head injuries, severehypertension, cerebral hypoxia, certain diseases of the eyes, nose,throat, teeth, and ears, and head pain for which no cause can bedetermined.

Infrequent headaches can often be determined to result from causesattributable to a particular experience of a patient, such as fatigue,fever, alcohol ingestion, muscle contraction, tension, or the like. Thecause of persistent or recurrent headaches is often difficult todetermine. Persistent or recurrent headaches include, but are notlimited to, muscular headaches, such as tension or muscle contractionheadaches, and neurovascular headaches, such as migraines and clusterheadaches.

Cerebral neurovascular disorders (CNvDs) are characterized by one ormore disturbances in the normal functioning of at least one component ofthe cerebral vascular or nervous system in a human. CNvDs include, forexample, migraine, cluster headaches, other headaches of neurovascularetiology, tinnitus, and cerebrovascular spasm. Human patients afflictedwith a CNvD experience a single episode of the disorder, recurrentepisodes, persistent episodes, or some combination of these patterns. Anindividual episode is designated an acute CNvD.

Many CNvDs, such as cerebral vascular accidents, reversible ischemicneurological defects, and transient ischemic attacks (TIA), areassociated with functional cerebral ischemia. These are oftennonhemorrhagic and of thrombotic, embolic, and vasospastic etiologies.Furthermore, intracranial vasospasm commonly afflicts patients who haveexperienced an acute cerebral ischemic event such as a stroke and isoften problematic following thrombolytic therapy. Numerous symptomsoccur during and after acute cerebral ischemic events. Indeed,neurovascular headaches have a vasomotor component to them, which may beresponsible for certain or many of the symptoms experienced by patientswho are afflicted with prolonged or recurrent neurovascular headachessuch as migraines and cluster headaches.

It has been theorized that headaches of neurovascular etiology, such asmigraines, for example, result from release of neurotransmitters bytrigeminal nerves, which innervate cerebral blood vessels (Moskowitz etal., 1979, Lancet 2:883-885). When disturbed, the trigeminal ganglion iscapable of antidromic release of excitatory and other neurotransmittersthat initiate sterile inflammation (Demarin et al., 1994, Funct. Neurol.9:235-245; Moskowitz, 1984, Ann. Neurol. 16:157-168; Moskowitz, 1993,Neurol. 43 (Suppl. 3):S16-S20). Studies of trigeminal stimulation,cerebral blood flow, and neuropeptides in animal models and in humansprovide support for this theory (Goadsby et al., 1993, Ann. Neurol.33:48-56; Goadsby et al., 1991, Headache, 31:365-370; Goadsby et al.,1990, Ann. Neurol. 28:183-187; Edvinsson et al., 1994, Cephalalgia14:88-96). It has been postulated that changes in cerebral blood flowthat are triggered by trigeminal stimulation are mediated by thesphenopalatine ganglion (hereinafter, the “SPG”) Goadsby et al., 1987,Am J. Physiol. 22:R270-R274; Lambert et al. 1984, J. Neurosurg.61:307-315; Walters et al., 986, Stroke 17:488-494; Suzuki et al., 1989Neuroscience 30:595-604).

Another theory posits that nitric oxide is a causative molecule ofheadaches of neurovascular etiology (Olesen et al., 1995, Cephalalgia15:94-100). Because the SPG and related postsynaptic and neurovascularstructures contain many cells which express nitric oxide synthetase, theSPG mediates the changes in cerebral blood flow that are triggered bytrigeminal stimulation, according to this model.

Regardless of whether a neurotransmitter, nitric oxide, both, or neitherare the causative agent of headaches of neurovascular etiology, it isclear that the SPG and other dorsonasal nerve structures are key complexstructures for targeting the treatment of headaches of neurovascularorigin, such treatment including, but not being limited to the treatmentof the pain associated with such headaches. Methods of treatingheadaches of neurovascular etiology which have been described in theprior art have not provided sustained and effective relief from acuteneurovascular headache episodes.

Other researchers have observed meningeal inflammation in the vicinityof head pain associated with migraine (Pappagallo et al., April 1999presentation, Meeting of the American Academy of Neurology, Toronto,Canada). Certain aspects of head pain associated with migraine (e.g.,throbbing headache, nausea, and sensitivity to light and sound) aresimilar to head pain associated with meningitis. Single photon emissioncomputerized tomography confirmed enhanced permeability of meningealblood vessels in patients experiencing migraine, which is a commonfinding among meningitis patients. It is believed by the inventor thatmeningeal inflammation may be associated with stimulation of, ortransmission by way of, the trigeminal nerve and related neuronalstructures.

Migraine

Migraine is a disorder characterized by persistent headache, which maybe severe, which may be associated with visual and gastrointestinaldisturbances, and which may also be recurrent. In certain cases, visualchanges (designated “aura” by some practitioners) or other symptomsprecede the onset of a migraine. Such prodromal symptoms may be due tointracranial vasoconstriction. The precise etiology of migraine isunknown. Reported evidence suggests that a genetically transmittedfunctional disturbance of intra- and extracranial circulation may beinvolved. Regional alterations in cerebral blood flow attributable tointracranial arterial vasodilation are known to accompany headacheassociated with migraine. Some investigators have attributed head painassociated with a migraine to substances released as a result of orassociated with dilation of scalp arteries during an acute migraineepisode (e.g., Berkow et al., ed., 1992, The Merck Manual of Diagnosisand Therapy, Merck Research Laboratories, Rahway, N.J., pp. 1425-1426).

Prodromal symptoms of an acute migraine episode include, but are notlimited to, depression, irritability, restlessness, anorexia,scintillating scotomas, visual changes such as perception of stars orzig-zag lines, paresthesias, and hemiparesis. These prodromal symptomsmay disappear shortly before the migraine is manifested, or may persistuntil or after the onset of the migraine.

The head pain associated with migraine may be unilateral or generalized.Nausea, vomiting, and photophobia often accompany migraines. Symptomsgenerally follow a pattern in an individual patient, except thatunilateral head pain may not always be on the same side. Patientsafflicted with migraine may experience migraines with a frequencybetween daily and only once in several months. An untreated acutemigraine episode may endure for a long period, such as hours or days.Approximately 17% of adult women and approximately 6% of adult menexperience migraines each year (Stewart et al., 1994, Neurol. (Suppl.4):S17-S23; Lipton et al., 1993 Neurology 43 (Suppl. 3):S6-S10;Osterhaus et al., 1992, PharmacoEconomics 2:67-76). Migraines may occurat any age, but usually begin between ages 10 and 30. Migraines oftenpartially or completely remit after age 50. Frequently, a history ofmigraines may be ascertained in the genealogy of a patient afflictedwith migraine.

Various nonspecific medical and surgical procedures have beenrecommended to decrease the frequency of recurrence of migraines. Suchprocedures include surgery, counseling, participation of the patient inbiofeedback procedures, and administration of methysergide, propanolol,a calcium channel blocker such as verapamil, an ergotamine preparationsuch as dihydroergotamine, or a serotonin receptor agonist such assumatriptan. Some procedures to decrease the frequency of recurrence ofmigraines may offer benefit to certain patients, but are not useful foralleviating the pain associated with an acute migraine episode once ithas begun.

Treatments which have been recommended for the treatment of an acutemigraine episode include administration of aspirin, codeine, a serotoninagonist such as sumatriptan, ergot, ergotamine, caffeine, a narcotic,butorphanol tartrate, meperidine, or a combination of these compounds.Administration of any combination of these compounds has not offeredsatisfactory or sustained relief from the pain or other symptomsassociated with an acute migraine episode in many patients. Furthermore,numerous side effects have been reported to accompany administration ofthese compounds, including dizziness, nausea, somnolence, fatigue, chestpain, cardiac infarction, hypertension, hypertensive crisis, chest-,face-, and neck-hyperemia, gastrointestinal upset, sedation, drugdependence, and the like. In addition, certain of these compounds arecontraindicated for numerous patients such as pregnant women, nursingwomen, patients using monoamine oxidase inhibitors, patients having ahistory of ischemic heart disease, ulcer, gastritis, kidney disease,liver disease, and other diseases.

Currently popular migraine treatments involve administration of apharmaceutically active agent which interacts with a serotonin receptoron cerebral arterial surfaces (Goadsby, 1995, In: Migraine: Pharmacologyand Genetics, Sandler et al., Eds., pp. 67-81; Cambridge et al., 1995,Brit. J. Pharmacol. 114:961-968; Ferrari et al., 1995, Euro. J. Neurol.2:5-21). Serotonin receptor agonists include sumatriptan (IMITREX™,Glaxo Wellcome Inc., Research Triangle N.C.), zolmitriptan (ZOMIG™,Zeneca Pharmaceuticals, Wilmington, Del.), and rizatriptan (MAXALT™,Merck & Co., West Point, Pa.). Serotonin receptor agonists are believedto produce relief from an acute migraine episode by causing resumptionof regulated cranial blood flow, thereby halting the acute migraineepisode (Hamel et al., 1993 Mol. Pharmacol. 44:242-246). However,administration of serotonin receptor agonists is inefficient viaintravenous, oral, and intrarectal gavage routes. These routes ofadministration result in systemic agonist distribution, which increasesthe availability of the agonist to hepatic tissue and to other siteswhere the agonists are metabolized. Furthermore, systemic distributionof one of an agonist results in distribution of the agonist to siteswhere the agonist produces undesirable side effects (Saper, 1997,Headache 37 (Suppl. 1):S1-S14). Therefore, it would be advantageous toadminister an agent which does not require systemic delivery.

Intranasal administration of lidocaine for the relief of pain associatedwith migraines has been investigated in a non-controlled study by Kudrowet al. (1995, Headache, 35:79-82). In that study, many patientsexperienced no relief and were on migraine prophylactic medication. In acontrolled study, Maizels and co-workers evaluated the effectiveness ofintranasally-administered lidocaine, a shorter-acting local anesthetic,for treatment of acute migraine episodes (Maizels et al., 1996, J. Amer.Med. Assoc. 276:319-321). High concentrations of lidocaine administeredintranasally decreased head pain within fifteen minutes in 55% of thepatients so treated. However, significant pain and associated symptomspersisted in many of these patients following treatment. A significantnumber of patients required further treatment with other types ofmigraine medication to attain acceptable relief. Furthermore, the acutemigraine episode frequently rebounded or relapsed early after treatment,usually within the first hour.

Cluster Headaches

A cluster headache comprises a headache which is characterized byrecurrent episodes of unilateral excruciating pain, usually occurring onthe same side of the head of a patient. These headaches are typicallyoculofrontal or oculotemporal, with occasional radiation to the upperjaw, and are described as being of a boring, non-throbbing nature.Associated with the head pain are one or more autonomic accompaniments,including conjunctival injection, nasal congestion, lacrimation,rhinorrhea, body temperature elevation, vasodilation on the same side asthat on which the pain is experienced, and edema beneath the eye. Acluster headache is usually of short duration, persisting for betweenfifteen and ninety minutes, and tends to occur in clusters—typically afew times a day for a period of six to twelve weeks. Months or years maypass between the clusters of headaches. Because headaches which appearto be identical to spontaneous cluster headaches may be induced bysubcutaneous injection of histamine diphosphate, cluster headaches arealso known as histamine headaches. Headaches having sensory similarityto cluster headaches may also be induced by administration ofnitroglycerin to a human patient, for example by sublingualadministration of 0.4 milligrams of nitroglycerin.

Methods which have been investigated for treating cluster headachesinclude administration of methysergide, a vasoconstrictor, acorticosteroid, oxygen, indomethacin, and intranasal administration ofcocaine, which is a toxic shorter-acting local anesthetic withpronounced central effects and a vasoconstrictor, or lidocaine, which isalso a shorter-acting local anesthetic (Barre, 1982, Headache, 22:69-73;Kittrelle et al., 1985, Arch. Neurol. 42:496-498). These investigationshighlight that shorter-acting local anesthetics were effective to abortpain associated with a single individual headache episode that is onlyone of several headache episodes comprising a cluster headache,sometimes referred to as a cluster period. Large amounts of drug andrepeated dosings were required to achieve these results. However, noinvestigation was made by those investigators of the ability of theseshorter-acting local anesthetics to provide relief from all, or evenmore than one, of the typically short-duration headaches associated witha single cluster headache period. Clinically, intranasal administrationof lidocaine has proven to be disappointing and is not widely used, noris it included in recognized cluster headache treatment protocols.

Tinnitus

More than 37 million Americans are afflicted with tinnitus. Tinnitus isa condition characterized by a ringing, buzzing, roaring, or clickingsound perceived by a patient, a person observing the patient, or both,which seems to originate from the ear of the patient. Objective tinnitusis characterized by noise originating from the ear of a patient whichcan be perceived by a person examining the patient, while noiseassociated with subjective tinnitus can be perceived only by thepatient. There are currently no truly effective treatment optionsavailable for tinnitus, which has been associated with instances ofsuicide in patients afflicted therewith. Treatment methods which havebeen attempted include surgical decompression of the eighth nerve, useof specialized hearing aids which mask the tinnitus, and infusion ofdrugs directly into areas of the brain involved in auditory sensoryprocessing. None of these treatment methods has proven routinelyeffective.

Intra- and Extracranial Vasospasm

Intra- and extracranial vasospasm, hereinafter referred to as“cerebrovascular spasm,” results from contraction of smooth muscletissue of a cerebral blood vessel. Cerebrovascular spasm interferes withcerebral blood supply and is associated with numerous symptoms,including muscle paralysis, visual changes, speech changes, and numerousischemic symptoms of stroke. Vascular muscle tone is modulated byneural, humoral and local factors.

Disorders Manifested During or after and Associated with an AcuteIschemic Event

Causes of acute ischemic events include occlusive (i.e., thrombotic orembolic) processes, as well as vasospastic and other physiologicalprocesses and disorders, following the onset of which the affectedtissue is insufficiently supplied with oxygenated blood. Manifestationsduring or after such events include, for example, tissue damage ordeath, vasospasm, vasodilation, vasomotor instability, muscle weakness,dysphasia, dysphonia, cognitive impairment, autonomic imbalance, and thelike. These disorders may be alleviated by increasing oxygenated bloodsupply to the ischemic tissue. Increased blood supply to ischemiccerebral tissue may be effected, for example, by inducing dilation of anoccluded cerebral blood vessel. Further by way of example, suchincreased blood supply may be effected by dilation of cerebral bloodvessels proximal to an occluded vessel by increasing the flow ofoxygenated blood or by increasing the pressure gradient across theocclusion, thereby decreasing the amount of watershed ischemia,decreasing the amount of damaged cerebral tissue, and increasing theamount of cerebral tissue which may be salvaged. Furthermore,facilitating venous drainage, by venodilation, decreases venous backpressure and increases forward flow of oxygenated blood.

Prior art methods of treating such disorders exhibit seriouslimitations. Thrombolytic therapy, for instance, is known to beeffective to decrease the severity of cerebral damage caused by certainocclusive strokes if the therapy is performed soon enough after theonset of the occlusion. However, cerebrovascular spasm frequentlyfollows, and decreases the success of the procedure and adverselyaffects patient outcome. A method of reducing the severity of an acutecerebral ischemic event by increasing early blood flow to the ischemicarea and decreasing vasospasm is needed.

Anatomy of the Nasal Cavity

The structures associated with the nasal cavity are described, forexample, in Williams et al. (eds., 1980, Gray's Anatomy, 36th ed., W.B.Saunders Co., Philadelphia, 1062-1065), especially at FIGS. 3.78, 3.79,3.80, 7.239, and 7.240 and the accompanying text. FIG. 1 herein is adiagram depicting the approximate location of the SPG in relation to thenasal cavity of a human.

The SPG is, in some texts, designated the “pterygopalatine ganglion.”The position, origin, branches, and distribution of the SPG may beunderstood by examining FIGS. 7.177, 7.178, 7.179, and 7.181 and theaccompanying text in Williams et al. (supra).

As the cited figures and text describe, the SPG is located below aregion of epithelium in the posterior portion of the nasal cavity,inferior to and including the spheno-ethmoidal recess, and is thereforenot readily accessible via the nostril.

Ropivacaine is a recently introduced amino amide local anesthetic thatis commercially available as the S(levo)-enantiomer (Lee et al., 1989,Anesth. Analg. 69:736-738). Ropivacaine allows differential nerve blockand exhibits intermediate distribution and clearance and a bettersystemic toxicity profile compared with other similar relatively longacting potent local anesthetics. In addition, ropivacaine also exhibitsinherent vasoactive properties (deJong, 1995, Reg. Anesth. 20:474-481;Santos et al., 1990, Anesth. Analg. 70:262-266). Ropivacaine-HCl iscommercially available as 0.25%, 0.5%, 0.75% and 1.0% (w/v) solution(NAROPIN™, Astra USA, Inc., Westborough, Mass.), and has been described,for example in international patent application publication number WO85/00599.

Local anesthetics are known to block the generation and the conductionof nerve impulses, presumably by increasing the threshold for electricalexcitation in the nerve, by slowing the propagation of nerve impulses,and by reducing the rate of rise of the action potential of the nerve.In general, the progression of anesthesia is related to the diameter,degree of myelination, and conduction frequency and velocity of affectednerve fibers. Generally, the order of loss of nerve function is asfollows: (1) sympathetic and parasympathetic function, temperature andpain, and (2) touch, and, where applicable, (3) proprioception, and (4)skeletal muscle tone.

The rate of systemic absorption in a patient of a local anesthetic isdependent upon the total dose, the concentration, and the identity ofthe local anesthetic administered to the patient, the route ofadministration, the vascularity of the site of administration, and thepresence or absence of vasoconstrictors such as epinephrine in theanesthetic composition. A dilute concentration of epinephrine (e.g.,1:200,000 or 5 micrograms per milliliter) usually reduces the rate ofabsorption and peak plasma concentration of the local anesthetic,sometimes prolonging the duration of the anesthetic effect.

The duration of the anesthetic effect at a given site of administrationof a local anesthetic is dependent upon the total dose, theconcentration, and the identity of the local anesthetic administered tothe patient, the rate of systemic absorption, and often the presence orabsence of a vasoconstricting or other agent in the anestheticcomposition.

Systemic administration of a local anesthetic is not a practical methodfor delivery of the local anesthetic to provide lasting relief ofheadache pain in a human patient, due to known adverse reactions,occasionally including acute emergencies, associated therewith.

There remains a significant unmet need for effective methods of treatingacute CNvDs such as persistent and recurrent headaches of neurovascularetiology, including migraines and cluster headaches. Particularly neededare compositions and methods which are effective for inhibiting an acuteneurovascular headache episode.

Muscular Headaches

Muscular headaches are very common in the adult population. It isestimated that between about 3% and about 5% of patients who experiencea muscular headache are afflicted with chronic muscular headaches, bywhich is meant that the muscular headache occurs more than fifteen daysper month for a period of at least about six months. Analgesic addictionis a recognized problem in the treatment of patients afflicted withchronic muscular headaches.

Muscular headaches may be acute, as is the case for typical episodictension headaches, which are related to contraction of muscles of thehead and neck. Sustained contractions of skeletal muscles of the head,neck, face, and shoulders are associated with concurrent local chemicalchanges within skeletal muscle, and may give rise to pain. The pain maybe localized or it may be referred, which means that the pain isperceived at a body location different than the location of musclecontraction. Muscle contraction headaches may also be chronic andassociated with depression or with one or more other psychologicalproblems. Muscle contraction headaches may also be associated withanatomic factors such as cervical arthritis, temporomandibular jointdisorders, irritating lesions, pressure and mechanical stress, eyestrain, or emotional stress or disorders.

Muscular headaches, including muscle contraction headaches and tensionheadaches, are recognized as the most common category of recurring headpain. In distinction from migraines, they are usually bilateral, oftenwith occipital nuchal, temporal, or frontal predominance or with diffuseextension over the top of the cranium. The pain may be located in theback of the head and neck as well. Unlike migraine pain, the painassociated with a muscular headache is usually described as squeezingand vise-like in nature. Nausea, photophobia, and phonophobia are notgenerally associated with muscular headache episodes. The onset of amuscular headache episode is more gradual than the onset of a migraineor cluster headache episode, and muscular headache episodes are notgenerally associated with auras or prodromal symptoms. The onset ofmuscular headache episodes does not appear to be associated withphysical activity by the patient. Once established, a muscular headacheepisode may persist, perhaps with minimal fluctuations in intensity, forweeks or months. Muscular headache is recognized as being present allday, day after day.

Although patients afflicted with migraine may be awaked from sleep,patients afflicted with a chronic muscular headache generally sleepundisturbed and perceive development or intensification of the headachesoon after waking. About a third of patients afflicted with a muscularheadache exhibit symptoms of depression. Migraine headaches may becomplicated by tension headaches which persist and arouse fears of masslesions, thereby leading to the performance of unnecessary diagnosticworkups in many patients.

Muscular headaches are recognized as being a distinct class ofheadaches, distinguishable from headaches such as migraines or clusterheadaches.

Muscular headaches are, in part, related to sustained contraction of theskeletal muscles of the scalp, face, neck, and shoulders. Sustainedmuscle contraction is related to local pathology, central influences,and multisystem modulation, and involves gamma efferent neuronal musclespindle activation. Related monosynaptic conduction through the ventralhorn augments both efferent neuronal discharge and muscle contraction. Acycle of pain, muscle spasm, local chemical changes, neuralexcitability, skeletal muscle blood vessel compression or spasm, andanxiety ensues. All types of persistent headaches lead to sustainedcranial muscle contraction, but pain resulting from this type ofsustained contraction is typified by an aching sensation, rather than bythe characteristic squeezing pain associated with muscular headaches.Sometimes, surface electromyograph recordings of the craniocervicalmuscles show no evidence of persistent contraction. It is thereforewidely suspected that muscular headaches are not caused solely bysustained cranial muscle contraction.

Generally, the pain associated with a muscular headache episode is mildto moderate in severity, although the pain becomes severe in manypatients. Relaxation, massage, and common analgesic medications such asaspirin and acetaminophen are often effective to alleviate mild muscularheadache pain. Codeine or other narcotic preparations, tranquilizers,and antidepressants are sometimes administered to patients experiencingmore severe muscular headache pain. Unfortunately, many of thesepatients develop physical dependence on these agents and must befollowed closely because of a significant incidence of addiction.

Nonetheless, the musculature of the head, neck, jaw, or upper back istense and tender in many or most patients afflicted with a muscularheadache, and one or more trigger points, or muscle knots, are oftenpresent. Cervical spine arthritis and temporomandibular joint disordersmay contribute to the development of a muscular headache.

Treatments which have been recommended for the treatment of muscularheadaches include reassurance and psychological support, massage of thehead and neck, application of hot and cold packs, transcutaneouselectrical neural stimulation, physical support (e.g., use of orthopedicpillows and the like), administration of aspirin compounds,acetaminophen compounds, non-steroidal anti-inflammatory drugs,tricyclic antidepressants, narcotic analgesics, oral muscle relaxants,with or without tranquilizers, muscle relaxants, and other analgesiccompounds. These treatments are generally effective for alleviatingmild- to moderate-intensity acute muscular headaches.

Some patients afflicted with either severe or chronic muscular headachessometimes experience relief from their acute symptoms using these knowntreatments. However, many do not. Furthermore, over time, many patientswho initially respond to one or more of these therapies become lessresponsive to these therapies, possibly because they develop a toleranceto known medications, or because the disease process progresses orincreases. Additionally, symptoms may be influenced by psychologicalfactors which may remain constant or worsen. The side effects whichaccompany administration of known medications are significant and maybecome more severe over time.

There remains a significant unmet need for effective compositions andmethods of treating muscular headaches, including inhibiting musclecontraction headaches and tension headaches. The present inventionprovides compositions and methods which satisfy this need.

Systemic Delivery of a Pharmaceutically Active Agent

Numerous pharmaceutically active agents are useful when deliveredsystemically to a human patient. Systemic delivery of such agents cansometimes be effected by oral administration of a composition comprisingthe agent. However, many pharmaceutically active agents are degraded by,or otherwise react with acids, proteins, or other agents located in, thehuman gastrointestinal tract or the human liver or circulatory system,with the result that the agent loses its pharmaceutical usefulness. Forthis reason, many pharmaceutically active agents may not practically beadministered by an oral route to achieve systemic delivery of the agent.In addition, gastrointestinal absorption of an orally administeredmedication may be impaired in a distressed patient, such as a patientexperiencing a migraine or any severe headache.

Pharmaceutically active agents intended for systemic delivery to a humanmay be administered via an intravenous route using well known methods.However, such methods cause discomfort to the patient and often can beperformed only in conjunction with frequent or continuous supervision bya medical professional.

Methods of topically administering compositions to a human tissue toachieve systemic delivery of a pharmaceutically active agent which is acomponent of the composition are known, including the use of transdermalor transmucosal pastes, cremes, liquids, solids and semisolidsimpregnated with the composition, and the like. Systemic delivery of apharmaceutically active agent effected by topical administration methodsare limited by the ability of the agent to diffuse through the tissue towhich the composition is applied to reach blood vessels where the agentis absorbed and taken up for systemic delivery.

A significant, unmet need remains for compositions and methods which canbe used to systemically deliver or to enhance systemic delivery of apharmaceutically active agent to a human and which overcome thelimitations of known systemic delivery compositions and methods.

The present invention provides compositions and methods which satisfythe needs described herein.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is a diagram depicting a sagittal section of a portion of a humanhead, the section being just to the right of the nasal septum. A sectionis cut away at the posterior portion of the nasal cavity to reveal theapproximate placement of the sphenopalatine ganglion. Indicia used inthis Figure include 12 inferior concha, 14 lower lip, 16 middle concha,18 maxillary nerve, 20 superior concha, 22 sphenopalatine ganglion, 24tongue, 26 trigeminal nerve, 28 uvula, and 30 upper lip.

FIG. 2 is a bar graph which depicts the percentage of patients whoexhibited at least 50% reduction in pain intensity following dorsonasaladministration of ropivacaine using the intranasal spray methoddescribed herein (“Nasal spray”), using the intranasal drip methoddescribed herein (“Nasal drip”), or using the intranasal cotton swabmethod described herein (“Sat'd Swab”).

FIG. 3 is a graph which depicts the percentage of patients who exhibitedat least 50% reduction in pain intensity following administration ofvarious pharmaceutically active agents. The response of patients to whoma placebo was a placebo is indicated by filled circles (●; data fromMaizels et al., 1996, J. Amer. Med. Assoc. 276:319-321 and TheSubcutaneous Sumatriptan International Study Group, 1991, New Eng. J.Med. 325:316-321); the response of patients to whom sumatriptan wasadministered (as described in The Subcutaneous Sumatriptan InternationalStudy Group, 1991, New Eng. J. Med. 325:316-321) is indicated by filledsquares; the response of patients to whom lidocaine was administered (asdescribed in Maizels et al., 1996, J. Amer. Med. Assoc. 276:319-321) isindicated by filled triangles; the response of patients to whomropivacaine was administered by nasal spray as described herein inExample 1 is indicated by filled inverted triangles; the response ofpatients to whom ropivacaine was administered by cotton swab asdescribed herein in Example 1 is indicated by filled diamonds.

FIG. 4, comprising FIGS. 4A through 4N, is a series of drawings whichdepict dorsonasal delivery apparatus of the invention. FIG. 4A is adiagram of a sagittal section through the right nostril and the rightportion of the nasal cavity of a human, illustrating the approximateplacement of the body 100 of the dorsonasal delivery apparatus describedherein. Abbreviations used in this Figure include apex A of the nasalcavity, nostril N, superior concha SC, middle concha MC, and inferiorconcha IC. FIG. 4B is a diagram of a coronal section through the nose ofa human taken along lines 4B-4B of FIG. 4A, illustrating the approximateplacement of a dorsonasal delivery device of the invention in the nasalcavity. FIG. 4C is a diagram similar to FIG. 4B, but depicting analternate embodiment of a dorsonasal delivery device of the presentinvention. FIGS. 4D through 4I illustrate various embodiments of thedorsonasal delivery device of the invention, as described herein.Alternative orientations of the device, before (solid) and after(dashed) inflation of the balloon 110 thereof are shown in FIG. 4G.FIGS. 4J and 4K, respectively, are diagrams of left and right side viewsof a dual-lumen dorsonasal delivery device described herein. FIGS. 4L,4M, and 4N are other embodiments of the dorsonasal delivery devicedescribed herein. In FIG. 4M, the position of an absorbent portion 110is shown alternatively in an engorged, extended position (solid) and acompressed position (dashed). In FIG. 4N, the absorbent portion 110 istapered in order to facilitate withdrawal from the nasal cavity withminimal trauma.

FIG. 5 is a diagram of an anatomically adapted dorsonasal deliverynozzle of the invention. The nozzle depicted in this Figure is adaptedfor the left nostril of a human patient.

FIG. 6 is a diagram of the orientation between the outlet port of theanatomically adapted dorsonasal delivery nozzle of the invention asshown in FIG. 5 and the apex of the nasal cavity of a human. The anglephi is indicated.

FIG. 7, comprising FIGS. 7A, 7B, and 7C, is a trio of diagrams depictingmanually pressure-actuated drug delivery devices having intranostrilapplicators. A prior art device is depicted in FIG. 7A, in whichactuating pressure is applied approximately coaxially with the nostril.In the devices of the invention, as depicted in FIGS. 7B and 7C,actuating pressure is not applied coaxially with the nostril.

BRIEF SUMMARY OF THE INVENTION

One aspect of the invention relates to a method of inhibiting a cerebralneurovascular disorder (CNvD) in a human patient. This method comprisesintranasally administering a long-acting local anesthetic pharmaceuticalcomposition to the patient in an amount effective to inhibit the CNvD.The CNvD may, for example, be selected from the group consisting oftinnitus, cerebrovascular spasm, seizure, a disorder manifested duringor after and associated with an acute ischemic event, and aneurovascular headache. Preferably, the CNvD is a migraine, such as anacute migraine episode.

According to this method, the long-acting local anestheticpharmaceutical composition comprises a pharmaceutically acceptablecarrier, at least one local anesthetic ingredient selected from thegroup consisting of a long-acting local anesthetic, a persistent localanesthetic, and a sustained release formulation of a local anesthetic,and may further comprise a compound selected from the group consistingof an anti-epileptic, phenyloin sodium, a serotonin receptor agonist, aserotonin subclass 5HT1F receptor agonist, LY334,370, a sesquiterpenelactone, parthanolide, Tanacetum parthenium, and an extract of Tanacetumparthenium.

The invention includes a method of inhibiting cephalic inflammation in ahuman patient. This method comprises anesthetizing a nerve structureassociated with the disorder in the patient for a period effective toinhibit the inflammation (e.g., at least about one or two hours). Thenerve structure can be anesthetized by any method known in the art ordescribed herein. For example, the nerve structure can be anesthetizedby performing acupuncture upon the nerve structure, applying anelectrical potential to the nerve structure, applying electromagneticradiation to the nerve structure, or administering a long-acting localanesthetic pharmaceutical composition to the nerve structure. In oneembodiment, cephalic inflammation is inhibited in the patient byenergizing a dorsonasally implanted electronic neural stimulator.

The invention also relates to an intranasal drug delivery device orapplicator. This device comprises a body having a shape which conformsto the shape of the nasal cavity of a human. The body has a proximal endand a distal portion having a distal end. The distal portion of the bodycan be urged through a nostril of the human into the apex of the nasalcavity without injuring the human. The distal end of the body may berounded. The body may, for example, be substantially rigid, be flexible,or comprise a flexible portion.

Optionally, a lumen extends longitudinally within the body of theintranasal drug delivery device or applicator of the invention. Thelumen extends from the proximal end thereof to an outlet port at theexterior surface of the body, such as an outlet port on the distalportion of the body. The lumen may extend to a plurality of outletports, or a plurality of lumens may extend longitudinally within thebody from the proximal end thereof to a separate outlet port.Preferably, at least one outlet port is situated on the distal portionof the body in an orientation such that when the distal portion of thebody is in the apex of the nasal cavity, the outlet port faces aposterior or superior portion of the nasal cavity, such as thesphenoethmoidal recess or the superior epithelial surface of the nasalcavity, so that directed intranasal delivery of the drug can beachieved.

The body of the intranasal drug delivery device of the invention may,for example, have an elongated shape selected from the group consistingof an angled shape and a curved shape. The longitudinal axis of the bodyat the distal end thereof forms an angle of about 90 to about 170degrees (preferably about 110 to about 160, and more preferably about120 to about 150 degrees) with the longitudinal axis of the body at theproximal end thereof.

In one embodiment of the intranasal drug delivery device of theinvention, the device further comprises an extendable instrumentsituated with a lumen thereof. The extendable instrument is extendablethrough the outlet port of the lumen. The extendible instrument may, forexample, be selected from the group consisting of a swab, a rosette, aninflatable balloon, and a needle. The needle may be hollow, have aoutlet in its distal end, extend through the lumen, or have a proximalend connectable to a reservoir, such as one selected from the groupconsisting of a compressible reservoir, a deformable bulb, and asyringe.

In another embodiment of the intranasal drug delivery device of theinvention, the body of the device has an absorbent portion on the distalportion thereof. In a separate embodiment, the device has a lumen whichcommunicates at the proximal end of the body with the interior of areservoir containing a pharmaceutical composition, such as one whichcomprises a long-acting local anesthetic. The pharmaceutical compositionmay, for example, be delivered in a form selected from the groupconsisting of a liquid, a gel, a foam, a mousse, a powder, a dispersedpowder, an atomized liquid, an aerosol, and a liposomal preparation.

The invention also relates to a method of intranasally (e.g.,dorsonasally) administering a composition to a human patient. Thismethod comprises inserting an intranasal drug delivery device of theinvention into a nostril of the patient, urging the device through thenostril such that the distal end of the body is in the apex of the nasalcavity, and contacting a portion of the nasal epithelium (e.g., aportion overlying the SPG) with the composition on the portion of theexterior surface.

The invention further relates to another method of intranasallyadministering a composition to a human patient. This method comprisesinserting an intranasal drug delivery device of the invention having alumen extending therethrough into a nostril of the patient, urging thedevice through the nostril such that the distal portion of the body isin the apex of the nasal cavity, and providing the composition to aportion of the nasal epithelium by way of the lumen.

The invention relates to still another method of intranasallyadministering a composition to a human patient. This method comprisesinserting an intranasal drug delivery device of the invention having alumen extending therethrough into a nostril of the patient, urging thedevice through the nostril such that the distal portion of the body isin the apex of the nasal cavity, urging an elongate instrumentcomprising the composition through the lumen (e.g., into the apex of thenasal cavity). The elongate instrument may, for example, be selectedfrom the group consisting of an extendable instrument comprising thecomposition, a swab impregnated with the composition, a rosetteimpregnated with the composition, a needle coated with the composition,an inflatable instrument comprising the composition, a balloon coatedwith the composition, a balloon impregnated with the composition, ahollow instrument having a lumen for providing the composition, and ahollow needle having a lumen for providing the composition, whereby thecomposition is provided to a portion of the nasal epithelium.

The invention also relates to an anatomically adapted intranasal (e.g.,dorsonasal) delivery nozzle for intranasally administering a compositionto a human patient. The nozzle comprises a body having a delivery lumenextending therethrough from a proximal end of the body to an outlet portat a distal portion of the body and an exterior portion. The exteriorportion has (i) a flattened portion situated peripherally between theproximal end and the distal portion for seating the nozzle against thenasal septum of the patient, (ii) an anterior portion situatedperipherally between the proximal end and the distal portion for seatingthe nozzle against a portion of the external nasal cartilage of thepatient, and (iii) an indented portion situated peripherally between theproximal end and the distal portion for seating the nozzle against anasal concha of the patient. When the nozzle is seated, the outlet portis situated within the nasal cavity of the patient such that the axisextending through the discharge port is offset from the apex of thenasal cavity by no more than about 30 degrees, and preferably by no morethan about 15 degrees. In an alternate embodiment, the body comprises adistal seating portion for seating the nozzle against the superiorsurface of the nasal cavity.

The body of the nozzle of the invention may, for example, be deformable.For example, the body may be deformable at a certain condition, but lessdeformable at a different condition. The nozzle may thus be adapted tothe nasal cavity of the patient at the certain condition and thereafterused at the different condition. By way of example, the body may beadapted to the nasal cavity of the patient at a temperature at which thebody is deformable, and thereafter used at a temperature at which thebody is less deformable.

The invention also relates to a method of intranasally (e.g.,dorsonasally) administering a composition to a human patient. Thismethod comprises seating within the nasal cavity of the patient ananatomically adapted intranasal delivery nozzle of the invention andthereafter providing the composition to the delivery lumen of thenozzle. The composition is thereby intranasally administered to thepatient.

The invention further includes an improved manually pressure-actuateddrug delivery device. The device comprises a body having an intranostrilapplicator for insertion into a nostril of a patient, a drug container,and a manually pressure-actuated actuator fixed to at least one of theapplicator and the container and actuatably fluidly connecting theapplicator and the container. Drug from the container is provided to theapplicator upon application of pressure by the patient to the connector.The improvement comprises the actuator being positioned with respect tothe intranostril applicator in such a way that actuating pressure mustbe applied to the actuator in a direction which is not co-linear withthe axis of the nostril into which the applicator is inserted.Alternatively, the actuator may be positioned with respect to theintranostril applicator in such a way that actuating pressure must beapplied to the actuator in a direction which is not parallel to the axisof the nostril. As another alternative embodiment, the actuator may bepositioned in such a way that actuating pressure must be applied to theactuator in a direction which is offset by at least about 30 degrees(preferably by at least about 45 degrees, at least about 60 degrees, orabout 90 degrees) from the axis of the nostril.

The invention further includes a systemic drug delivery device. Thisdevice comprises a body having a shape which conforms to the shape ofthe nasal cavity of a human. The body has a proximal end and a distalportion which can be urged through a nostril of the human into the apexof the nasal cavity without injuring the human. The body also has anapplicator portion in the form of at least one of a portion on which thedrug is present, a portion to which the drug may be supplied, and alumen through which the drug may be delivered. The applicator portion isadapted for location in close anatomic proximity to a highlyvascularized portion of the nasal epithelium when the distal portion ofthe body is in the apex of the nasal cavity.

The invention still further includes an anatomically adapted intranasaldelivery nozzle for systemically administering a composition to a humanpatient. This nozzle comprises a body having a delivery lumen extendingtherethrough from a proximal end of the body to an outlet port, and anexterior portion. The exterior portion has (i) a flattened portionsituated peripherally between the proximal end and the distal portionfor seating the nozzle against the nasal septum of the patient, (ii) ananterior portion situated peripherally between the proximal end and thedistal portion for seating the nozzle against a portion of the externalnasal cartilage of the patient, and (iii) an indented portion situatedperipherally between the proximal end and the distal portion for seatingthe nozzle against a nasal concha of the patient. When the nozzle isseated, the outlet port is situated within the nasal cavity of thepatient such that the axis extending from the discharge port extendsthrough a highly vascularized portion of the nasal epithelium.

The invention also includes a method of inhibiting a cerebralneurovascular disorder in a human patient. This method comprisesenergizing a dorsonasally implanted electronic neural stimulator.

The invention also includes local anesthetic compound having thechemical structure of formula (IV), wherein R is ethyl, phenyl, or C₅-C₈straight- or branched-chain alkyl, and R′ is 2,6-dimethylphenyl,thiophene, or 2,5-dimethylthiophene, and wherein R″ and R″′ are selectedsuch that either (i) each of R″ and R″′ is a straight-chain alkylwherein R″ and R″′ have a total of 4 to 6 carbon atoms, or (ii) R″ andR″′ together form a heteroalkyl ring having a total of 5 to 7 carbonatoms and a nitrogen atom

For example, the local anesthetic compound may have the structure offormula (III)

In the structures of formulas (III) and (IV), the carbon atom indicatedby the asterisk is a chiral center.

The invention also relates to a kit comprising the long-acting localanesthetic pharmaceutical composition of the invention and an intranasaldrug delivery device or applicator for administering the composition tothe patient. For example, the device or applicator may be one of thosedescribed herein, and can be adapted for dorsonasal delivery. The kitmay also comprise instructional material which describes intranasal ordorsonasal administration of the composition to a human or anotheranimal.

DETAILED DESCRIPTION OF THE INVENTION

The first aspect of the present invention is based on the discovery thatintranasal administration of a long-acting local anestheticpharmaceutical composition to a human patient experiencing a cerebralneurovascular disorder (CNvD) inhibits the CNvD or a symptom of theCNvD. The invention also relates to the discovery that anesthesia of adorsonasal nerve structure (DnNS) in a human patient experiencing a CNvDinhibits the CNvD or a symptom of the CNvD if the anesthesia persistsfor a period of at least about an hour, and preferably for a period ofat least about two hours.

Local anesthetics are known to provide analgesia to a body surface towhich they are applied. However, such analgesia persists only for aperiod of time which is characteristic of the particular localanesthetic used and the site anesthetized. Local anesthetics may beroughly divided into classes based on the duration of analgesia providedto a patient following topical administration.

It is known that intranasal administration of a relativelyshorter-acting local anesthetics such as lidocaine or cocaine decreaseshead pain for a period approximately equal to the duration of analgesiawhich is characteristic of such shorter-acting local anesthetics.Lidocaine and cocaine each exhibit a duration of action shorter thanabout one hour when intranasally administered.

What was not known, and what represents a surprising discovery, is thatintranasal, and preferably dorsonasal, administration of a localanesthetic preparation which either relieves a symptom of the CNvD forat least about one hour or exhibits a duration of anesthesia equal to atleast about one hour is effective both to relieve head pain beyond theperiod of expected anesthesia and, more importantly, to inhibit theCNvD, such that symptoms of the CNvD, including head pain, do notrebound following the period of anesthesia, or even for many hours,days, or weeks thereafter. Rebound remains a major shortcoming of priorart treatments. It has furthermore been discovered that cephalicinflammation, a condition associated with CNvDs (as a symptom, as acause, or both) can be inhibited by interrupting or interfering withneural transmission of neural impulses through one or more DnNSs, suchas by intranasally (and preferably dorsonasally) administering along-acting local anesthetic pharmaceutical composition to the patient,by applying an electrical potential to the DnNS, or by any otheranesthetic method described herein.

Prior art intranasal delivery devices (e.g., intra-nostril squeeze-typemist dispensers) typically deliver compositions to only the distalportions of the nose, such as to portions of the nasal mucosa within afew centimeters of the nares. Devices disclosed herein can be used todirect compositions to other portions of the nasal cavity, including toportions of the nasal epithelium that contact or overlie importantphysiological structures, such as nerves, other nervous tissues, andblood and lymphatic vessels in the superior and dorsal portions of thenasal cavity. The devices can also be used to target particularstructures.

DEFINITIONS

As used herein, the term “cerebral neurovascular disorder” (CNvD) meansa disorder which is characterized by one or more disturbances in thenormal functioning of at least one component of the cerebral vascular orcerebral nervous system in a human. CNvDs which have been characterizedinclude migraine, cluster headaches, other headaches of neurovascularetiology, tinnitus, and cerebrovascular spasm. An “acute” CNvD means anindividual episode of a CNvD. Thus, an acute CNvD includes, but is notlimited to, an acute neurovascular headache episode, a single episode oftinnitus, a single episode of cerebrovascular spasm, and a set ofsymptoms or a disorder manifested during or after and associated with anacute ischemic event such as a single cerebrovascular occlusion or astroke.

As used herein, cephalic inflammation includes, but is not limited to,cerebral inflammation, meningeal inflammation, and other varieties ofextracranial and intracranial inflammation.

As used herein, a CNvD or an acute CNvD or a muscular headache is“inhibited” if at least one symptom of an episode of the CNvD or themuscular headache is alleviated, terminated, or prevented. As usedherein, a CNvD or muscular headache is also “inhibited” if the frequencyof recurrence, the severity, or both, of acute CNvD or muscular headacheis reduced.

As used herein, the term “muscular headache” means head, neck, face,periocular, scalp, or upper back pain associated with contraction ofmuscles of the head, neck, jaw, or upper back of a patient. The headpain may be experienced in or around a muscle, or it may be referred toa part of the head or upper back distinct from the site of the affectedmuscle. It is understood that the term “muscular headache” includes bothacute and chronic episodes of head pain. By way of example, muscularheadaches include muscle contraction headaches and tension headaches.

As used herein, a CNvD or a muscular headache is “terminated” if atleast one symptom of the CNvD or muscular headache ceases in a patientand the patient does not experience the symptom for at least severalhours or, preferably, for at least about one day.

As used herein, a “recurring” CNvD is a CNvD which is experienced by apatient more than once in a six-month period

As used herein, the term “acute ischemic event” refers to a singleepisode experienced by a human patient wherein a tissue of the patientis insufficiently supplied with oxygen. Acute ischemic events include,for example, ischemia associated with a stroke, ischemia associated withvasospasm, and ischemia associated with an acute neurovascular headacheepisode.

As used herein, the term “neurovascular headache” means a headache ofneurovascular etiology associated with a disease, disorder, or imbalanceof the nervous or vascular systems in a human. Headaches ofneurovascular etiology include, but are not limited to, migraines andcluster headaches.

As used herein, the term “acute neurovascular headache episode” means asingle neurovascular muscular headache which either has a durationgreater than about one hour or recurs more than once in a one-day periodin a human patient. Examples of acute neurovascular headache episodesinclude, but are not limited to, a single persistent neurovascularheadache, an acute migraine episode, each of the individual headacheepisodes associated with a recurrent neurovascular headache, and each ofthe individual headache episodes associated with a cluster headache.

As used herein, the term “acute muscular headache episode” means asingle muscular headache. Examples of acute neurovascular headacheepisodes include, but are not limited to, a single muscle contractionheadache and a single tension headache.

As used herein, the term “chronic muscular headache” means a muscularheadache muscular which is experienced by a human patient more thanfifteen days per month for a period of at least about six months.

As used herein, the term “persistent neurovascular headache” means aheadache of neurovascular etiology which persists for a period longerthan about one hour.

As used herein, the term “recurrent neurovascular headache” means aheadache of neurovascular etiology which is experienced by a humanpatient more than once in a one-day period.

As used herein, the term “rebound” of a CNvD means experience by apatient of one or more symptoms of the CNvD following a period duringwhich the patient did not experience the one or more symptoms, thesymptom-free period having been preceded by an earlier period duringwhich the patient experienced one or more symptoms of the CNvD. It isunderstood that it is not always possible to discern whether a patientwho did not experience the one or more symptoms for a period isafflicted with the same episode or with a separate episode of the sameCNvD. Thus, the term is inclusive of both situations.

As used herein, the term “migraine” means a human disorder characterizedby at least one persistent neurovascular headache episode.

As used herein, the term “an acute migraine episode” means an individualheadache experienced by a human patient afflicted with migraine.

As used herein, the term “cluster headache” means a human disordercharacterized by recurrent neurovascular headaches of short duration.

As used herein, the term “individual headache episode associated with acluster headache” means a single neurovascular headache experienced by ahuman patient afflicted with cluster headache.

As used herein, the term “prodromal headache symptom” means a symptomwhich is experienced by a patient and which is associated with the onsetor indicates the imminent onset of an acute neurovascular headacheepisode.

As used herein, a “nerve structure” means a nerve, a plurality of nerveslocated in close anatomic proximity to one another, or a ganglion.

As used herein, a nerve structure is “associated with” a CNvD if, whenthe nerve structure is anesthetized in a human patient afflicted withthe disorder, the patient experiences relief from at least one symptomof the CNvD.

As used herein, a “dorsonasal nerve structure” (DnNS) means thesphenopalatine ganglion (SPG) or a nerve structure located in closeanatomic proximity to the SPG.

As used herein, a first nerve structure is located in “close anatomicproximity” to a second nerve structure if the second nerve structure isanesthetized following anesthesia of the first nerve structure effectedby administration of a local anesthetic to a tissue which comprises oroverlies the first nerve structure. It is believed that dorsonasaladministration of a local anesthetic anesthetizes at least one, andperhaps all, of the SPG, the cavernous sinus ganglion, the carotic sinusganglion, numerous branches of the maxillary nerve, the ethmoidal nerve,the ethmoidal ganglion, and the vidian nerve. Thus, by way of example,each of the cavernous sinus ganglion, the carotic sinus ganglion,numerous branches of the maxillary nerve, the ethmoidal nerve, theethmoidal ganglion, and the vidian nerve is located in close anatomicproximity to the SPG, and thus each is a DnNS.

As used herein, an “intranasal nerve structure” (“InNS”) is a nervestructure that contacts the nasal epithelium or lies in sufficientlyclose proximity to the nasal epithelium that a compound applied to theepithelium is able to diffuse to or otherwise gain access to the nervestructure.

As used herein, an “intranasal blood vessel” (“InBV”) is a blood orlymphatic vessel that contacts the nasal epithelium or lies insufficiently close proximity to the nasal epithelium that a compoundapplied to the epithelium is able to diffuse to or otherwise gain accessto the blood vessel.

As used herein, a nerve structure is “anesthetized” when the capacity ofthe ganglion to generate or conduct nerve impulses is significantlyimpaired, relative to the capacity of the nerve structure to generate orconduct nerve impulses in the absence of intervention, such as byadministration of a local anesthetic. Anesthesia of the SPG effected byadministration of a local anesthetic, for example, interrupts thefunctioning normally associated with the SPG and with other DnNSs. It isunderstood that anesthesia of a nerve structure may be achieved not onlyusing a local anesthetic, but also by any anesthetic method as set forthherein.

As used herein, the capacity of a DnNS to generate or conduct nerveimpulses is “significantly impaired” when that capacity is reduced by anamount sufficient to relieve the pain associated with a headache ofneurovascular origin in a patient afflicted with such a headache.

As used herein, the term “shorter-acting local anesthetic” means a localanesthetic which, when intranasally administered to a human patientexperiencing a CNvD or a muscular headache, relieves at least onesymptom of the CNvD or muscular headache for a period of less than aboutone hour. By way of example, lidocaine and cocaine are shorter-actinglocal anesthetics.

As used herein, the term “long-acting local anesthetic” means a localanesthetic which, when intranasally administered to a human patientexperiencing a CNvD or a muscular headache, reliably or consistentlyrelieves at least one symptom of the CNvD or muscular headache for aperiod of at least about one hour. By way of non-limiting examples,bupivacaine and ropivacaine are long-acting local anesthetics.

As used herein, the term “persistent local anesthetic” means a localanesthetic which, when intranasally administered to a human patientexperiencing a CNvD or a muscular headache, relieves at least onesymptom of the CNvD or muscular headache for a period of at least abouttwo hours.

As used herein, the terms “vasoconstrictor” and “vasoconstricting agent”are used interchangeably to mean an agent which induces diminution ofthe lumenal caliber of a blood vessel. The agent may be a chemicalcompound or a stimulus applied to a motor neuron which causesvasoconstriction. Hence, administration of a vasoconstrictor maycomprise administration of a chemical compound, application of such astimulus, or both. Vasoconstrictors include, but are not limited to,epinephrine, norepinephrine, and phenylephrine.

As used herein, the terms “vasodilator” and “vasodilating agent” areused interchangeably to mean an agent which induces an increase in thelumenal caliber of a blood vessel.

As used herein, the term “intranasal administration” of a compositionand grammatical forms thereof mean delivery of the composition to anyportion of the nasal epithelium.

As used herein, the term “dorsonasal administration” of a compositionand grammatical forms thereof mean delivery of the composition to atissue, fluid, or surface of a human, whereby a component of thecomposition is provided to a DnNS or to a tissue overlying a DnNS.Dorsonasal administration may be accomplished, for example, by topicaladministration of the composition to the region of the nasal epitheliumoverlying the SPG or to the surface of the nasal epithelium near theregion of the nasal epithelium overlying the SPG, whereby a component ofthe composition is capable of diffusing through any tissue or fluidwhich may be interposed between the surface and the SPG. Suchadministration may also be accomplished, for example, by injecting thecomposition directly into the SPG or by injecting the composition intoor otherwise administering the composition to a tissue or fluid near theSPG, whereby a component of the composition is capable of diffusingthrough any tissue or fluid which may be interposed between the site ofinjection or administration and the SPG.

As used herein, the term “the region of the nasal epithelium overlyingthe SPG” means the area of the nasal epithelium having a geometricalrelationship with the SPG whereby an imaginary line approximatelyperpendicular to the surface of the epithelium and extending from thesurface of the epithelium in the direction of the basement membrane ofthe epithelium passes through a DnNS.

As used herein, the term “the surface of the nasal epithelium near theregion of the nasal epithelium overlying the SPG” means a portion of thesurface of the nasal epithelium which is continuous with andsufficiently geometrically close to the region of the nasal epitheliumoverlying the SPG such that a compound applied anywhere on this surfaceis able to diffuse to the SPG. It is understood that the boundaries ofthe surface are dependent upon the diffusivity of the compound in theepithelium and in any tissue or fluid situated between the epitheliumand the SPG. Thus, the area of this surface will be greater for acompound having high diffusivity than the area corresponding to acompound having a lower diffusivity. It is further understood that,where the compound has a half-life in vivo, the boundaries of “thesurface of the nasal epithelium near the region of the epitheliumoverlying the SPG” are dependent upon the half-life of the compound.Thus, the area of this surface will be greater for a compound having alonger half-life than the area corresponding to a compound having ashorter half-life.

In the case of a compound having a diffusivity and a half-lifecomparable to that of ropivacaine, “the surface of the nasal epitheliumnear the region of the epithelium overlying the SPG” includes, but isnot limited to, the surface of the region of the nasal epitheliumoverlying the SPG and the surface of the nasal epithelium continuouswith and located within about three centimeters of that region.Preferably, such a compound is delivered to the surface of the nasalepithelium within about two centimeters of that region, and even morepreferably to the surface of the nasal epithelium within about onecentimeter of that region. Most preferably, the compound is delivered tothe surface of the nasal epithelium overlying the SPG. It is understoodthat, in the case of a local anesthetic such as ropivacaine, the surfaceincludes the epithelial surface covering the dorsal surface of the nasalcavity extending caudally from approximately the superior extent of thesphenoethmoidal recess to approximately the inferior boundary of thenasopharynx and extending laterally between the region of the surfacecovering the perpendicular plate of the right palatine bone and theregion of the surface covering the perpendicular plate of the ethmoidbone and between the region of the surface covering the perpendicularplate of the left palatine bone and the region of the surface coveringthe perpendicular plate of the ethmoid bone.

As used herein, the “superior portion” of the nasal epithelium means oneor more areas of the nasal epithelium situated on or above the superiorface of the superior conchae.

As used herein, the term “non-intravenous administration” of acomposition means administration of the composition by any means otherthan injection or infusion of the composition directly into thebloodstream of a human patient.

As used herein, the term “long-acting local anesthetic pharmaceuticalcomposition” means a chemical composition comprising a pharmaceuticallyacceptable carrier and at least one local anesthetic ingredient selectedfrom the group consisting of a long-acting local anesthetic, apersistent local anesthetic, and a sustained release formulation of alocal anesthetic, wherein administration of the composition to a patientexperiencing a CNvD or muscular headache inhibits the CNvD or muscularheadache.

As used herein, the term “pharmaceutically acceptable carrier” means achemical composition with which a local anesthetic may be combined andwhich, following the combination, can be used to administer the localanesthetic to a human patient without significantly adversely affectingthe patient.

As used herein, “a sustained release formulation of a local anesthetic”is a pharmaceutical composition comprising a local anesthetic, whereinupon administration of the composition to a tissue of a human patient,the local anesthetic is delivered to the tissue on a continuous orsemi-continuous basis for a period of hours, days, or weeks. Methods ofmaking and using sustained release formulations of local anesthetics arewell within the skill of one of ordinary skill in the art ofpharmacology. In addition, inclusion of a vasoconstrictor in thecomposition may prolong the duration of the anesthetic effect.

As used herein, a composition is “formulated for intranasal delivery” ifthe composition is susceptible of intranasal administration to a humanand if the composition is not significantly injurious to the tissueslining the nasal cavity of a human.

As used herein, the term “pharmaceutically active agent” means acomposition which, when administered to a human patient, has abiochemical or physiological effect on the patient.

As used herein, “instructional material” includes a publication, asound, video, or other recording, a diagram, or any other medium ofexpression which can be used to communicate the usefulness of thecomposition of the invention for inhibiting a CNvD or a muscularheadache. The instructional material of the kit of the invention may,for example, be separate from, included with, or affixed to a containerwhich contains the composition of the invention or be shipped togetherwith a container which contains the composition. The instructionalmaterial may, for example, describe an appropriate dose of thecomposition of the invention or directions for using an applicatorincluded in the kit to intranasally or dorsonasally administer a localanesthetic.

As used herein, a “eutectic mixture” is a mixture comprising at leastone local anesthetic and at least one eutectic ingredient.

As used herein, a “eutectic ingredient” is a chemical compound which,when mixed with a local anesthetic, yields a mixture having a meltingpoint lower than the melting point of the local anesthetic.

As used herein, a body has a shape which “conforms to” the nasal cavityof a human if the shape of the elongate body is, or becomes uponinsertion into the nasal cavity, similar to the shape of the nasalcavity.

DESCRIPTION OF THE INVENTION Inhibition of a Cerebral NeurovascularDisorder

One aspect of the invention is based on the discovery that intranasal,and preferably dorsonasal administration of a long-acting localanesthetic pharmaceutical composition to a human patient experiencing acerebral neurovascular disorder (CNvD) inhibits the CNvD. Thelong-acting local anesthetic pharmaceutical composition comprises alocal anesthetic ingredient selected from the group consisting of along-acting local anesthetic, a persistent local anesthetic, and asustained release formulation of a local anesthetic. The duration ofrelief from a symptom of a CNvD effected by intranasal administration ofthe long-acting local anesthetic pharmaceutical composition according tothis method is at least about one hour, and is preferably at least abouttwo hours. However, the duration may be at least about seventy-five,ninety, one hundred and five, or any other number of minutes such thatthe effective duration of relief is greater than that effected byintranasal administration of either lidocaine or cocaine. Inhibition ofa CNvD may include inhibition of one or more symptoms or aspects of theCNvD. By way of example, inhibition of a CNvD includes inhibition ofcephalic inflammation associated with the CNvD.

Intranasal, and preferably dorsonasal, administration of at least onelong-acting or persistent local anesthetic, such as bupivacaine orropivacaine, to a human patient experiencing a CNvD is sufficient toinhibit the CNvD or a symptom of the CNvD. Furthermore, intranasal ordorsonasal administration of a composition comprising a sustainedrelease formulation of a shorter-acting local anesthetic inhibits theCNvD or a symptom thereof. By way of example, the CNvD may be aneurovascular headache, tinnitus which does not accompany aneurovascular headache, a cerebrovascular spasm which does not accompanya neurovascular headache, or an acute CNvD.

Symptoms of an acute neurovascular headache episode which can beinhibited by intranasal or dorsonasal administration of a long-actinglocal anesthetic pharmaceutical composition include, but are not limitedto, head pain, cephalic inflammation (e.g., cerebral inflammation,meningeal inflammation, and inflammation of the hypothalamus or otherportions of the brain), tinnitus, visual changes, phonophobia,photophobia, nausea, seizure, cerebrovascular spasm, symptoms of acuteischemic events, such as muscle weakness, dysphasia, dysphonia,cognitive impairment, autonomic imbalances, and the like.

Prior art methods of treating an acute CNvD often transiently and/orincompletely relieve head pain, the primary symptom of many CNvDs. Incontrast, the compositions, kits, and methods of the present inventionprovide lasting and effective relief of the symptoms of a CNvD. Withoutwishing to be bound by any particular theory, it is believed thatintranasal administration of a long-acting local anestheticpharmaceutical composition to a patient experiencing a CNvD providesrelief by inhibiting the physiological processes underlying the CNvD,whereby both the CNvD and symptoms of the acute CNvD are inhibited.

Prevention of an Acute Cerebral Neurovascular Disorder

The method described herein for inhibiting an acute CNvD includes amethod of preventing a CNvD, including a method of preventing one ormore symptoms (e.g., cephalic inflammation) associated therewith.Certain CNvDs, particularly migraines, are associated with prodromalsymptoms which are experienced by a patient prior to the onset of thedisorder. By treating a patient using the method described herein forinhibiting a CNvD at a time when the CNvD is expected or at a time whena prodromal symptom of the CNvD is experienced by the patient, the CNvDmay be prevented.

Decreasing the Frequency and/or Severity of Recurring CNvDs

Numerous cerebral CNvDs including, but not limited to migraines andTIAs, are characterized by periodic or irregular recurrence. Over time,severity of CNvDs often seems to increase and many CNvD-afflictedpatients seem to experience CNvD episodes more frequently. It wasobserved that the frequency of recurrence and severity of CNvD episodesdecreased with time in patients using the compositions and methodsdescribed in the present disclosure, even after treatment was no longeradministered. These phenomena have not been previously observed with anyother CNvD treatment method, including any migraine treatment method.The compositions, kits, apparatus, and methods of the invention areuseful for decreasing the frequency of recurrence, the severity, orboth, of CNvD episodes experienced by a patient afflicted with recurringCNvDs such as migraines and TIAs.

The invention thus includes a method of decreasing the frequency orseverity with which CNvD episodes are experienced by a patient afflictedwith a recurring CNvD. The method comprises intranasally, and preferablydorsonasally, administering to a patient experiencing a CNvD episode along-acting local anesthetic pharmaceutical composition. The compositioncomprises a local anesthetic which is preferably a long-acting localanesthetic, a persistent local anesthetic, or a sustained releaseformulation of a shorter-acting or a long acting or a persistent localanesthetic, and is preferably administered to the patient early in thecourse of the CNvD episode. Preferably, the local anesthetic isadministered to the patient within two hours following the onset of theepisode, more preferably within one hour, and even more preferablywithin thirty minutes of the onset. Early administration provides moreprompt relief, but administration of the local anesthetic according tothis invention may be at any time with good results.

Other Acute Cerebral Neurovascular Disorders

Intranasal, and preferably dorsonasal, administration of a localanesthetic can also be used to treat any CNvD, in addition to migrainesor other neurovascular headaches. Examples of acute CNvDs other thanacute neurovascular headache episodes include, but are not limited to,tinnitus, seizures or seizure-like activities, cerebrovascular spasm,cephalic (e.g., meningeal) inflammation, and disorders manifested afterand associated with an acute ischemic event such as a stroke, reversibleischemic neurological deficit, or transient ischemic attack. The localanesthetic compounds, formulations, dosages, and methods ofadministration which are useful for inhibiting these CNvDs aresubstantially the same as those described herein with respect toinhibiting a neurovascular headache. Where the acute CNvD is associatedwith cerebral ischemia, the amount of brain tissue which experiencesischemic damage may be reduced by this method.

Stimulation of DnNSs such as the trigeminal nerve can induce releasefrom the DnNS of peptides and other neurotransmitters and humoralfactors such as nitric oxide. Some of these neurotransmitters andhumoral factors resemble (or are identical to) compounds released frominjured, hyper-stimulated, or growing nerves. These compounds can inducemeningeal inflammation, and can, over time, induce anatomic andphysiologic changes which facilitate pathways that allow more efficienttransmission of nociceptive impulses and that lower triggeringthresholds. Thus, if release or endurance of these compounds in thevicinity of the DnNS is not minimized, the DnNS can becomehypersensitized, with the result that the CNvD recurs more frequently orreadily. Release of compounds which induce meningeal inflammation can beminimized, as described herein, by anesthetizing the DnNS for aneffective period of at least about one hour, and preferably two hours.Release of such compounds may also be minimized by providing a serotonin(5HT) agonist or another pharmaceutical agent to the DnNS, preferably inconjunction with the long-acting local anesthetic pharmaceuticalcomposition. These two agents may, for example, be administered in theform of a single pharmaceutical composition comprising both along-acting local anesthetic composition and a 5HT agonist (e.g.,sumatriptan, zolmitriptan, rizatriptan, or naratriptan), or in the formof two separate pharmaceutical compositions (e.g., an intra- ordorsonasally administered long-acting local anesthetic pharmaceuticalcomposition and an oral 5HT agonist) having overlapping periods ofbiological effect. When the 5HT agonist is administered locally (e.g.,dorsonasally) to the DnNS, onset time of the pharmacological effect ofthe agonist may be reduced and duration of the pharmacological effect ofthe agonist may be extended by administering the agonist in conjunctionwith a vasoconstrictor. Furthermore, uptake of the 5HT agonist may befurther improved by including the R-enantiomer of the local anesthetic(e.g., R-bupivacaine or a mixture of the R- and L-enantiomers ofbupivacaine, such as a mixture wherein about 5-30% of bupivacaine isR-bupivacaine) in the composition. An optimum concentration may be used,wherein a more effective, powerful, and prolonged nerve block can beobtained, while also allowing increased uptake of any co-administeredpharmaceutical agent.

The local anesthetic compounds, formulations, dosages, and methods ofadministration which are useful for inhibiting these CNvDs aresubstantially the same as those described herein with respect toinhibiting a neurovascular headache. Where the acute CNvD is associatedwith cerebral ischemia, the amount of brain tissue which experiencesischemic damage may be reduced by this method.

Tinnitus, cephalic inflammation, and these other CNvDs may also beinhibited by anesthetizing a DnNS using alternate anesthetic methodsincluding, but not limited to, transcutaneous electrical neuralstimulation, electromagnetic techniques, application of radio frequencyradiation, and surgical intervention to sever or disrupt the DnNS.

Duration of Anesthetic Effect

It has been discovered that intranasal administration of a long-actinglocal anesthetic pharmaceutical composition is necessary in order toinhibit a CNvD in a human patient. That is, intranasal administration ofrelatively shorter-acting local anesthetic compositions, such as alidocaine-containing composition which is not a sustained releaseformulation, provides only transient relief (i.e., less than about onehour) from CNvD symptoms, without inhibiting the CNvD.

It is preferable that the long-acting local anesthetic pharmaceuticalcomposition of the invention, when administered intranasally, andpreferably dorsonasally to a patient experiencing a CNvD, inhibits atleast one symptom of the CNvD for a period of at least about one hour.Thus, as described herein, compositions comprising bupivacaine orropivacaine are effective for inhibiting a CNvD when administeredintranasally to a patient, while compositions comprising lidocaine in anon-sustained release formulation are not effective for inhibiting aCNvD. Thus, the long-acting local anesthetic pharmaceutical compositionpreferably comprises a local anesthetic ingredient which relieves atleast one symptom of a CNvD for a period greater than the period ofrelief provided by intranasal administration of lidocaine, and morepreferably relieves the symptom for at least about as long asropivacaine.

It is believed that anesthesia of a DnNS for a period of at least aboutone hour, or preferably at least about two hours, results in inhibitionof both the symptoms and the physiological processes of a CNvD,including sterile inflammation and vascular lability, associated withneurovascular headache episodes such as migraines and cluster headaches.Thus, for example, a migraine and its accompanying symptoms may beinhibited by intranasally, and preferably dorsonasally, administering along-acting local anesthetic, a persistent local anesthetic, or asustained release formulation of a local anesthetic to a patientexperiencing the migraine and its symptoms. Preferably, the period isone which is effective to terminate these processes, whereby both theprocesses and the symptoms associated with the CNvD are terminated.

At least one investigator (Barre, 1982, Headache 22:69-73) hasinvestigated the use of cocaine, a toxic, addictive, shorter-actinglocal anesthetic with well-known potent central nervous systemproperties, to relieve the pain associated with an individual headacheepisode associated with a cluster headache.

The addictive, toxic, and central nervous system excitatory qualities ofcocaine render it an inappropriate treatment in virtually all currentclinical settings. Hence, it is preferable that the local anestheticused in the method of the invention be a local anesthetic other thancocaine. Thus, it is preferred to use a long-acting local anesthetic, apersistent local anesthetic, or a sustained release form of ashorter-acting local anesthetic other than cocaine in the methods of theinvention.

Prior art investigations have examined the effectiveness of lidocaine, ashorter-acting local anesthetic, for providing relief from headaches ofneurovascular origin (Kittrelle et al., 1985, Arch. Neurol. 42:496-498;Kudrow et al., 1995, Headache, 35:79-82; Maizels et al., 1996, J. Amer.Med. Assoc. 276:319-321). These investigations involved intranasaladministration of 4% (w/v) lidocaine, wherein the doses were sometimesrepeated. Although many patients in these studies experienced a shortterm decrease in head pain, a significant number of these patientsrequired supplemental medication with other known headache therapeuticagents and the rate of rebound was high.

Not recognized by these investigators was the fact that theirinvestigations were hampered by the incapacity of lidocaine to provideconsistent, long-lasting relief from the CNvD for a period of at leastabout one hour. Hence, although intranasal administration of highconcentrations of lidocaine provided short term pain reduction, theacute neurovascular headaches experienced by the patients worsened orrebounded when the anesthetic effects of lidocaine subsided, withinabout an hour. Any effect which long-acting local anesthetics might havehad upon inhibiting acute neurovascular headache episodes in thepatients involved in those investigations was not recognized. The factthat no further development of lidocaine or its derivatives as theprimary pharmaceutically active agent for persistent or recurringneurovascular headache relief was pursued, despite the critical need forsuch agents, is further evidence that the importance of the period ofinhibition of at least one symptom of the CNvD, such as a period on theorder of at least about one hour, and preferably at least about twohours, was not recognized as being useful to abort the physiologicpathology of sterile inflammation and vasomotor instability which, whennot aborted, triggers another headache episode upon subsidence of theanesthetic effect of the shorter-acting local anesthetic.

The results of studies by Kudrow et al. (1995, Headache, 35:79-82),Maizels et al. (1996, J. Amer. Med. Assoc. 276:319-321), and Bane (1982,Headache 22:69-73) can be explained by the model of CNvDs presentedherein, wherein a DnNS such as the SPG is involved in the pathogenesisof headaches of neurovascular etiology. None of these prior art studiesrecognized that the severely limited effectiveness of intranasaladministration of either lidocaine or cocaine for the alleviation ofpain associated with a headache of neurovascular etiology was due to thefact that lidocaine and cocaine are merely shorter-acting localanesthetics when used in this manner. Indeed, repeat doses of cocaineand lidocaine were needed to treat individual and subsequent shortduration headache episodes associated with a cluster headache.

Inhibition of a CNvD such as an neurovascular headache requiresintranasal, and preferably dorsonasal, administration of a long-actinglocal anesthetic pharmaceutical composition which provides relief from asymptom of the CNvD for a period longer than that effected by thetreatments in the investigations of Kudrow et al., Maizels et al., andBarre, namely for a period of at least about one hour, and preferably atleast about two hours.

Shorter-acting local anesthetics are not consistently or reliablyeffective for inhibiting a CNvD when administered in a single dose or inmultiple doses administered over a short period of time such as a fewminutes. Nonetheless, using the teachings of the present invention, itis possible to use shorter-acting local anesthetics in a manner moreeffective to inhibit a CNvD without causing the side effects associatedwith repetitive dosing of these agents at high concentration. In orderto inhibit a CNvD, it is necessary that a shorter-acting localanesthetic be intranasally, and preferably dorsonasally, administered asa sustained release formulation, or that an additional compound whichextends the duration of anesthesia effected by the shorter-acting localanesthetic, such as epinephrine or another vasoconstrictor, beco-administered to the patient. Preferably the additional compound isadministered to the patient in a composition comprising the localanesthetic and the additional compound. Compounds, formulations, anddosages of the vasoconstrictors described in this method are known inthe art. For example, vasoconstrictive compositions may be used atart-recognized effective doses, such as, about 0.001 milligram permilliliter to about 0.01 milligram per milliliter of epinephrine.Similarly, the other additional compounds described in this paragraphmay be used at art-recognized effective doses.

Theory Proposed to Explain the Efficacy of the Compositions and Methodsof the Invention for Inhibiting a Neurovascular Headache

It should be appreciated that the superiority of the compositions andmethods of the invention relative to the compositions and methods of theprior art does not depend upon the accuracy of the theory offered toexplain the superior results.

While not wishing to be bound by any particular theory of operation, itis believed that intranasal administration of the composition of thepresent invention inhibits a neurovascular headache by anesthetizing adorsonasal nerve structure (DnNS) in the patient for a period effectiveto inhibit the physiological processes that result in the neurovascularheadache, such as a period on the order of at least about an hour, andpreferably at least about two hours.

Still without wishing to be bound by any particular theory, it isbelieved that the following model explains the physiological processesunderlying an acute neurovascular headache. An acute neurovascularheadache generation center (ANvHGC) is located in the pons of the humanbrain, near the locus coeruleus. The ANvHGC initiates an excitatorysignal which affects the reticular formation, the trigeminal nerve, andsympathetic, parasympathetic, and other outflows from the midbrain andpons. Trigeminal nerve fibers innervate cerebral blood vessels andmodulate vasomotor function and intra- and extracranial blood vesseltone and communicate with multiple neural structures. Stimulation of thetrigeminal nerve by the ANvHGC results in changes in efferent andafferent neural activity and changes in regional intracranial bloodflow. Many factors, including stimulation of the trigeminal nerve by theANvHGC, facilitate neurogenic inflammation and associated vasomotor andother changes, including, but not limited to, monocytic and lymphocyticinfiltrates, perivascular edema, and release of neurohumoral and otherchemical factors. This results in intra- and extracranial neural andvascular hyperexcitability. This hyperexcitability decreases thethreshold for neuronal and humoral signaling and other triggers whichinduce further vasospasm or further neuronal hyperexcitability andaltered efferent and afferent activity. Prolonged vasospasm leads totissue ischemia, which induces further release of neurohumoral factors,increases perivascular edema, and exacerbates neurogenic inflammation.These local neurovascular changes induce greater neuronal and vascularhyperexcitability. All of these factors contribute to thepathophysiologic cycle of neurovascular headache.

Altered cerebral blood flow, neurogenic inflammation, and associatedvasomotor and other changes are experienced by the patient as head pain,tinnitus, symptoms of cerebrovascular spasm such as visual changes,blindness, or disorientation, or some combination of these, andcontribute to the prodromal and other symptoms of an acute neurovascularheadache. Data obtained recently by Pappagallo et al. (supra) confirmthat inflammation (presumably neurogenic) of the meninges is associatedwith head pain in patients experiencing migraine.

Even in the absence of head pain, intracranial and extracranial bloodvessel hyperexcitability and neuronal hyperexcitability can lead torecurrence or rebound of an acute neurovascular headache, such as amigraine, or to prolongation of the physiology of the neurovascularheadache cycle. Thus, an alternate neurovascular headache cycle mayinclude a period during which symptoms of the neurovascular headache arenot perceived by the patient, but during which period intracranial andextracranial blood vessels and nerves remain hyperexcitable, as in thecase of a series of individual headache episodes associated with acluster headache or a recurrent migraine.

Further, without wishing to be bound by any particular theory, it isbelieved that intranasal administration of a shorter-acting localanesthetic such as lidocaine or cocaine merely provides analgesia aloneby inhibiting transmission of nerve impulses for a relatively shortperiod—less than about an hour. Administration of a shorter-acting localanesthetic does not interrupt the physiological processes which causethe pain associated with an acute CNvD such as an acute neurovascularheadache episode. The duration of the anesthetic effect of ashorter-acting local anesthetic such as lidocaine is too short to permitintracranial and extracranial blood vessels and nerves to recover fromthe hyperexcitable state. The duration of the anesthetic effect of ashorter-acting local anesthetic is also too short to allow clearance ofvascular and perivascular humoral and cellular factors fromcerebrovascular tissue. The result of the short duration of theanesthetic effect of a shorter-acting local anesthetic is that theneurogenic inflammation continues, the neurovascular headache cyclepersists, and, once the anesthetic effect of the shorter-acting localanesthetic subsides, the neurovascular headache rebounds.

In contrast, in accordance with the present invention, anesthesia of aDnNS such as the SPG for an effective period that permits intracranialand extracranial nerves and intracranial and extracranial blood vesselsto recover from the hyperexcitable state, arrests neurogenicinflammation, and permits clearance of vascular and perivascular humoraland cellular factors from cerebrovascular tissue, inhibits thephysiological processes which cause the occurrence or persistence of anacute neurovascular headache. The effective period of such anesthesiamust be sufficient to affect these physiological processes in abeneficial manner, such as a period on the order of at least about anhour, and preferably at least about two hours. It is understood that theeffective period may vary among individuals.

Compromised cerebral vascular flow volume and neurogenic inflammationare believed to be related to neural and humoral factors includingincreased local concentrations of nitric oxide, vasoactive intestinalpeptide (VIP), substance P, and other factors present in ischemic orinflamed tissue. It is believed that the mechanism by which neurogenicinflammation is arrested and recovery of nerves and blood vessels fromtheir hyperexcitable state is permitted following anesthesia of a DnNS,such as the SPG, for an effective period of time involves neuronalstabilization and clearance from intra- and extracranial neuronal andvascular tissues of nitric oxide, VIP, substance P, one or moreneurotransmitters, one or more peptides, cellular infiltrates, or acombination of these factors. Concomitantly, blood vessel permeabilityis normalized and perivascular edema decreases. Anesthesia of the DnNSfor the effective period furthermore limits release of humoral agents incerebrovascular tissue and decreases vasoconstriction and, by inhibitionof neural mediated increases in blood vessel smooth muscle tone, mayeffect vasodilation, thereby permitting dissipation of local humoral andcellular factors associated with head pain and other symptoms. Theresult is that when the anesthetic effect of the local anestheticsubsides, the cranial nerves and vascular structures are no longerhyperexcitable, neurogenic inflammation has been arrested or reversed,local humoral and cellular factors have dissipated, and thus theneurovascular headache cycle does not continue or rebound. This modelrepresents a possible explanation of the superiority of the compositionsand methods of the invention for inhibiting an acute neurovascularheadache, relative to the compositions and methods of the prior art,which were ineffective or of very limited effectiveness for inhibitingsuch disorders.

The ability to block nerve fibers which mediate the processes involvedin the headache cycle varies with the particular local anesthetic used.Shorter-acting local anesthetics do not exhibit the same degree ofdifferential blockade (i.e., sensory blockade compared with autonomicblockade) exhibited by long-acting and persistent local anesthetics.Without wishing to be bound by any particular theory, it is believedthat the anti-neurovascular headache efficacy exhibited by long-actingand persistent local anesthetics, relative to the non-efficacy ofshorter-acting local anesthetics, may be attributable in whole or inpart to the degree of differential blockade capabilities exhibited bythese types of local anesthetics.

One aspect of the present invention may be explained, at least in part,by the hypothesis that intranasal, and preferably dorsonasal,administration of a long-acting local anesthetic pharmaceuticalcomposition inhibits an acute CNvD such as an acute neurovascularheadache episode. This treatment is hypothesized to result in anesthesiaof a DnNS such as the SPG for a period of at least about one hour, andpreferably for a period of about two hours.

Anesthesia of a DnNS such as the SPG may be achieved in any of a numberof ways. For example, at least one long-acting or persistent localanesthetic may be intranasally or dorsonasally administered to a patientto effect anesthesia of the DnNS. Further by way of example, a sustainedrelease formulation of a shorter-acting, long-acting, or persistentlocal anesthetic may be dorsonasally administered to a patient to effectanesthesia of the DnNS. Any method known in the art of anesthetizingnerves may be used to anesthetize the DnNS. Further by way of example,acupuncture techniques, application of electrical potential to a DnNS,or application of electromagnetic radiation, such as light or radiofrequency radiation, to a DnNS may be used to anesthetize the DnNS.Intranasal, and preferably dorsonasal, administration of a long-actinglocal anesthetic pharmaceutical composition is a preferred method ofinhibiting a CNvD.

Inhibition of a migraine by dorsonasal administration of at least onelocal anesthetic is an effective means of arresting the cascade ofmigraine development with consequent sterile inflammation and protractedmultisystem aggravation of symptoms, particularly where such anesthesiapersists for a period of at least about an hour, and preferably at leastabout two hours. Any of the pharmaceutical compositions described hereinmay be used for dorsonasal administration of the local anesthetic, usingthe dosages and formulations herein. As will be understood by oneskilled in the art, the optimal dosage and formulation for use with anindividual patient depends upon the age, size, condition, state ofhealth, and preferences of the patient, as well as upon the identity ofthe local anesthetic. Selection of optimal doses and formulations are,in view of the present disclosure, well within the skill of the ordinaryartisan.

Inhibition of a CNvD, a symptom of the CNvD, or both, occur very rapidlyfollowing intranasal or dorsonasal administration of a long-acting orpersistent local anesthetic such as ropivacaine. Half maximal inhibitionoccurs within about three minutes, and the rate of rebound isnegligible. Photophobia and nausea are inhibited at the same time aspain following dorsonasal administration of ropivacaine. Thecoincidental effect may be due to the wide ranging effects of intranasaladministration of the composition of the invention on multiple subpialand cerebrovascular systems. By contrast, the migraine therapeuticeffects of a serotonin receptor agonist depends on the ability ofvascular flow to effect an effective concentration of the agonist at thesite of the compromised cerebral blood vessels. The serotonin receptoragonists show intersubject variance in efficacy due to the biphasicnature of the relationship between the concentration of the agonist andthe physiological effect in vascular structures. Serotonin receptoragonists also exhibit variable efficacy due to variable effect ofindividual serotonin receptor agonists upon blood vessels within themajor cerebrovascular and subpial structures of a patient.

Combining a long-acting local anesthetic pharmaceutical composition witha serotonin receptor agonist will have an additive, if not synergisticeffect on therapeutic efficacy because the disease process is inhibitedby different mechanisms. In particular, serotonin receptor subclass5HT1F agonists (e.g., LY334,370) are noteworthy in their decreased sideeffect profile and decreased efficacy, relative to serotonin receptorsubclass 5HT1D agonists, and may be used in combination with ananesthetic in a long-acting local anesthetic pharmaceutical composition,such as that described herein. Such a composition will exhibit increasedefficacy, relative to the serotonin receptor subclass 5HT1F agonistalone, regardless of the dose of the agonist.

Recurring CNvDs lead to cumulative damage and neurological defects amongpatients afflicted with these CNvDs. For example, certain patients whoare afflicted with recurring migraines sustain permanent neurologicaldamage. Without wishing to be bound by any particular theory, it ispostulated that anatomic and physiologic pathologies may be secondary tothe cumulative effects of repetitive pain stimuli, pain impulses,ischemia, sterile inflammation, related processes, or some combinationof these. Effective management of the neurovascular ischemic componentof a recurring CNvD may decrease cumulative neurological damageattributable to the CNvD episodes. For example, ending the ischemiccomponent of a migraine promptly after the onset of the acute migraineepisode may decrease the damage and deficit exhibited in certainophthalmic, basilar, or other migraine patients. Compromised nervestructures have a lower threshold of neuronal signaling to restartsubsequent CNvD episodes. Thus, decreasing the cumulative neurologicaldamage attributable to recurring CNvD episodes decreases the frequencywith which CNvD episodes are experienced by the patient.

Further without wishing to be bound by any particular theory, the painand other neuronal signals transmitted by cerebral nerve structuresduring a CNvD episode may predispose the same or other nerve structuresto onset of a subsequent CNvD episode by processes analogous to“neuronal learning” or to central sensitization and amplification.Neuronal learning is a theory which has been described by others toexplain the apparent self-facilitating nature of pain generation andsensation. The theory of neuronal learning postulates that thetransmission of pain impulses by a particular neural pathway predisposesthat particular neural pathway to future transmission of pain impulsesin response to triggers or impulse-generating stimuli of lower magnitudethan would normally be required for pain sensation. Noxious stimuli canalso cause lasting central sensitization whereby altered sensoryprocesses in the central nervous system amplify, even in the distantfuture, subsequent pain. By way of example, it has been demonstrated insurgical patients that pre-surgical central neurologic blockade (e.g.,using epidural analgesia) reduces the sensation of postoperative pain inthe patients, even up to more than nine weeks following surgery,relative to patients who receive identical central neurologic blockadepostoperatively (Gottschalk et al., 1998, J. Amer. Med. Assoc.279:1076-1082; Woolf et al., 1993, Anesth. Analg. 77:362-379; Shis etal., 1994, Anesthesiology 80:49-56). It is believed that failure toblock transmission of pain impulses from surgically-affected sensoryneurons in the postoperatively blocked patients lowers the thresholdsensation needed to trigger pain impulse transmission from these neuronsor facilitates central amplification of pain. In contrast, it isbelieved that blockade of transmission of pain impulses from the samesurgically-affected sensory neurons in presurgically blockaded patientsprevents this threshold-lowering effect.

While still not wishing to be bound by any particular theory, it isbelieved that dorsonasal administration of a long-acting or persistentlocal anesthetic at an early stage of a CNvD episode blocks thetransmission of pain impulses from, through, or both, relevant cerebralor other neurological structures, such that these neurologicalstructures therefore do not experience the threshold-lowering affectattributable to neuronal learning. The amount of stimulation that willinduce a subsequent episode of a CNvD is thereby not lowered.Additionally, there is no central amplification of perceived pain.Because the threshold stimulation required for inducement of CNvDepisodes is not lowered, and further because there is no centralamplification of pain, patients treated using the compositions, kits,and methods of the invention are less predisposed to subsequent CNvDepisodes, and the frequency and severity of any subsequent CNvD episodesis reduced.

Intranasal, and preferably dorsonasal, administration of a long-actinglocal anesthetic pharmaceutical composition can also be used to reducethe severity of an acute cerebral ischemic event, thereby decreasingneurologic deficits resulting therefrom. Without wishing to be bound byany particular theory of operation, it is believed that the followingproposed mechanism explains the efficacy of this method. Tissue damagecaused by an acute ischemic event is mediated by a shortage of oxygen insuch tissue. This tissue damage may be alleviated in at least two ways.Damage may be alleviated by counteracting the cause of the tissuehypoxia or by inducing supplementary oxygen delivery to the tissue.Intranasal administration of a local anesthetic is believed to reducethe severity of an acute cerebral ischemic event in both of these ways.It is believed that intranasal administration of a local anestheticinterrupts the neural component which contributes to the vasospasmassociated with an acute cerebral ischemic event. Relief of this neuralcomponent of the event can reduce or eliminate ischemia associated withthe event. Furthermore, it is believed that vasodilatory effects ofintranasally administered local anesthetics cause dilation of bloodvessels supplying the ischemic tissue, decreasing the degree of vesselocclusion, thereby increasing blood supply to the ischemic tissue. Thesevasodilatory effects may also increase blood flow through the bloodvessel occlusion, for example by dilating proximal blood vessels,thereby increasing the pressure gradient across the occlusion, resultingin less watershed ischemia.

Inhibition of Muscular Headaches

Another aspect of the present invention is based on the discovery thatintranasal, and preferably dorsonasal, administration of a localanesthetic to a human patient experiencing a muscular headache issufficient to inhibit the muscular headache or a symptom associatedtherewith. Preferably, the local anesthetic is a long-acting orpersistent local anesthetic, but shorter-acting local anesthetics arerecognized as being effective to inhibit a muscular headache as well,using this method.

Prior art methods of treating a muscular headache have focused on usingacetylsalicylic acid and its derivatives, non-steroidalanti-inflammatory drugs, sedatives, narcotics, and other drugs todecrease head pain, the primary symptom of muscular headaches.

What was not known, and what represents a surprising discovery, is thatintranasal, and preferably dorsonasal, administration of a localanesthetic, preferably one which exhibits a duration of anesthesia equalto at least about a few minutes, is effective both to relieve head painduring the period of anesthesia and, more importantly, to inhibit amuscular headache.

Although all types of head pain, even head pain associated with diverseclasses of headaches, may have similar aspects of presentation,character, or pathophysiology, muscular headaches are recognized as aseparate class of headache, with distinct characteristics (HeadacheClassification Committee of the International Headache Society, 1988,Cephalalgia 8 (Suppl. 7):19-28).

It has not previously been recognized that local anesthetics, whenadministered intranasally or dorsonasally, were capable of relievingmuscular headache pain or muscle spasm associated with muscularheadaches.

The present invention also includes a method of inhibiting a muscularheadache episode in a human patient, the method comprising intranasally,and preferably dorsonasally, administering to the patient a compositioncomprising a local anesthetic and an analgesic or other pharmaceuticallyactive agent. Preferably, the local anesthetic is not cocaine, andadministration of the composition results in relief of a symptom of themuscular headache and further results in improved delivery of theanalgesic or other agent to a cerebral neurovascular tissue of thepatient. By way of example, the agent may be aspirin, acetaminophen, anon-steroidal anti-inflammatory drug, a tricyclic antidepressant, ananxiolytic, a serotonin agonist such as a triptan or a chroman compound,a narcotic, or a drug that increases cerebral levels ofgamma-aminobutyric acid. Compounds, formulations, and dosages ofanalgesics and other pharmaceutically active agents described in thismethod are known in the art. Owing, in part, to the vasodilatoryactivity of local anesthetics, these compounds may be used according tothis method at doses of about half their art-recognized doses to theirfull art-recognized doses.

The method described herein for treating a muscular headache episode canalso be used to prevent such an episode. Certain muscular headaches canbe reliably predicted to occur following particular patient activitiesprior to the onset of the episode. By treating a patient using themethod described herein for treating a muscular headache episode at atime when the episode is expected, at a time when the patient is underemotional distress, or at a time when the patient is exposed to anotherheadache-triggering condition, the muscular headache episode may beprevented.

It is believed that the compositions and methods of the inventionprovide more rapid and complete relief of muscular headache symptomsthan do known compositions and methods. Furthermore, intranasal anddorsonasal administration of local anesthetics are not associated withthe side effects known to be associated with prior art headachetreatments, and do not induce tolerance, as do prior art headachetreatments. Thus, besides being a useful headache treatment in itself,the method of the invention is a useful alternative or adjunctivetherapeutic modality with regard to prior art muscular headachetreatments.

Theory Proposed to Explain the Efficacy of the Compositions and Methodsof the Invention for Inhibiting a Muscular Headache

It should be appreciated that the superiority of the compositions andmethods of the invention relative to the compositions and methods of theprior art does not depend upon the accuracy of the theory offered toexplain the superior results. Regardless of the mechanism by whichmuscular headaches are generated, intranasal, and preferably dorsonasal,administration of a local anesthetic, preferably a long-acting orpersistent local anesthetic, inhibits a muscular headache.

Without wishing to be bound by any particular theory, it is believedthat the following model explains the physiological processes underlyinga muscular headache. It is believed that non-desirable sustained musclecontraction is related to local pathology, central influences andmultisynaptic modulation, and involves gamma efferent neuronal musclespindle activation. Related monosynaptic conduction through the ventralhorn augments both efferent neuronal discharge and muscle contraction. Amuscular headache cycle of pain, muscle spasm, local chemical changes,neuronal excitability or hyperexcitability, skeletal muscle blood vesselcompression or spasm, and anxiety ensues.

Anesthesia of a DnNS such as the SPG effected by dorsonasal delivery ofa topical anesthetic is an effective means of inhibiting a chronicmuscular headache, particularly where such anesthesia persists for aperiod of at least about an hour, and preferably at least about twohours. Anesthesia of the DnNS and consequent relief of associatedsymptoms occurs very rapidly following intranasal or dorsonasaladministration of a long-acting or persistent local anesthetic such asropivacaine. Half maximal arrest occurs within about three minutes. Theeffect may be due to the wide ranging effects of DnNS anesthesia onmultiple subpial and cerebrovascular systems. For example, thetrigeminal nerve is in communication with upper cervical nerves,particularly cervical nerve 2. Interruption of efferent or afferentlimbs of cervical nerve 2 would inhibit facial and scalp skeletal musclespasm, thereby breaking a major component of the muscular headachecycle.

Anesthesia of a DnNS such as the SPG for a period of at least about afew minutes, preferably at least about one hour, and more preferably atleast about two hours, may be achieved in any of a number of ways. Forexample, a shorter-acting local anesthetic may be intranasally ordorsonasally administered to a patient to effect anesthesia of the DnNSfor a period of less than about one hour, it being understood that suchtreatment may be effective only to alleviate a muscular headacheepisode, possibly without inhibiting the episode. Also by way ofexample, a long-acting or persistent local anesthetic may beintranasally or dorsonasally administered to a patient to effectanesthesia of the DnNS. Further by way of example, a sustained releaseformulation of a shorter-acting, long-acting, or persistent localanesthetic may be dorsonasally administered to a patient to effectanesthesia of the DnNS. Any method known in the art of anesthetizingnerves may be used to anesthetize the DnNS. Further by way of example,acupuncture techniques, application of electrical potential to a DnNS,or application of electromagnetic radiation, such as light or radiofrequency radiation, to a DnNS may be used to anesthetize the DnNS.

Local Anesthetics

The chemical identity of the local anesthetic or anesthetics used in thecompositions and methods of the invention is not critical. As describedherein, long-acting or persistent local anesthetics may be administeredin pharmaceutically acceptable carriers, and shorter-acting localanesthetics may be administered in sustained release formulations or inconjunction with an additional compound which extends their anestheticeffect.

Compounds having local anesthetic activity which may be used to practicethe invention include, but are not limited to, articaine, ambucaine,amolanone, amylocaine, benoxinate, betoxycaine, biphenamine,bupivacaine, levo-bupivacaine, butacaine, butamben, butanilicicaine,butethamine, butoxycaine, carticaine, 2-chloroprocaine, cocaethylene,cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethocaine,diperodon, dyclonine, ecgonidine, ecgonine, ethyl aminobenzoate, ethylchloride, etidocaine, levo-etidocaine, dextro-etidocaine, beta-eucaine,euprocin, fenalcomine, fomocaine, hexylcaine, hydroxyprocaine,hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate,levoxadrol, lidocaine, lidocaine salicylate monohydrate, meperidine,mepivacaine, levo-mepivacaine, meprylcaine, metabutoxycaine, methylchloride, myrtecaine, naepaine, octacaine, orthocaine, oxethazaine,parethoxycaine, phenacaine, phenol, pipecoloxylidides, piperocaine,piridocaine, polidocanol, pramoxine, prilocalne, procaine, propanocaine,proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine,quinine urea, risocaine, ropivacaine, levo-ropivacaine, salicyl alcohol,sameridine, tetracaine, tolycaine, trimecaine, veratridine, andzolamine, as well as 2-alkyl-2-alkylamino-2′,6′-acetoxylidide compounds,such as those described in U.S. Pat. No. 3,862,321; glycerol1,2-bis-aminoalkyl ether compounds, such as those described in U.S. Pat.No. 4,117,160; benzisoxazole compounds, such as those described in U.S.Pat. No. 4,217,349; O-aminoalkylsalicylate compounds, such as thosedescribed in U.S. Pat. No. 4,298,603; heterocyclic phenoxyaminecompounds, such as those described in U.S. Pat. No. 4,379,161; 2- and3-aryl substituted imidazo(1,2-A) pyridine compounds, such as thosedescribed in U.S. Pat. No. 4,871,745, in U.S. Pat. No. 4,833,149, and inU.S. Pat. No. 4,727,145; polyorganophosphazene compounds, such as thosedescribed in U.S. Pat. No. 4,495,174 and in U.S. Pat. No. 4,636,387;tertiary-alkylamino-lower acyl-xylidide compounds, such as thosedescribed in U.S. Pat. No. 3,925,469; amidinourea compounds, such asthose described in U.S. Pat. No. 4,147,804; 3-(5′-adenylates) oflincomycin-type or clindamycin-type compounds, such as those describedin U.S. Pat. No. 4,397,845; N-substituted derivatives of1-(4′-alkylsulfonylphenyl)-2-amino-1,3-propanediol compounds, such asthose described in U.S. Pat. No. 4,632,940; tertiary aminoalkoxyphenylether compounds, such as those described in U.S. Pat. No. 4,073,917;adenosine compounds, such as adenosine and adenosine mono-, di-, andtriphosphate; lauryl polyglycol ether compounds, such as those describedin U.S. Pat. No. 5,676,955 and mixtures of such ether compounds;2-(omega-alkylaminoalkyl)-3-(4-substituted-benzylidene) phthalimidinecompounds or 2-(omega-dialkylaminoalkyl)-3-(4-substituted-benzylidene)phthalimidine compounds, such as those described in U.S. Pat. No.4,551,453; N,N,N-triethyl-N-alkyl ammonium salts, such as thosedescribed in U.S. Pat. No. 4,352,820; L-N-n-propylpipecolicacid-2,6-xylidide compounds, such as those described in U.S. Pat. No.4,695,576; N-substituted 4-piperidinecarboxamide compounds, such asthose described in U.S. Pat. No. 5,756,520; N-substituted4-phenyl-4-piperidinecarboxamide compounds, such as those described inU.S. Pat. No. 5,360,805; polymers comprising repeating units of one ormore local anesthetic moieties, such as polymers described in U.S. Pat.No. 3,914,283; compounds of formula (I):

and its derivatives, such as those described in International PatentApplication Publication No. WO 97/38675; compounds of formula (II):

wherein R₁₋₄, m, and P are defined as in International PatentApplication Publication No. WO 95/21821; compounds having a structuredescribed in International Patent Application Publication No. WO97/15548; compounds having a structure described in International PatentApplication Publication No. WO 97/23467; compounds having a structuredescribed in U.S. Pat. No. 4,870,086; compounds having a structuredescribed in U.S. Pat. No. 4,529,601; long-acting topical anestheticagents; long-acting topical anesthetic products of Astra {Astra Zeneca}of the “LTA” series of compounds; ester forms of any of these compounds,salts of any of these compounds, compounds otherwise chemically relatedto one of these compounds which would be effective in the presentinvention; and sustained release preparations of any of these agents, asdescribed herein. Also included are derivatives of the foregoing, wherethe derivative is any chemically related compound effective for thepresent invention.

Synonyms, including chemical names, chemical formula, and trade names,for many of the local anesthetics described herein may be found inPhysician's Desk Reference® (Medical Economics Co., Inc., Montvale,N.J., 51st ed., 1997) or in PDR® GENERICS™ (Medical Economics Co., Inc.,Montvale, N.J., 2nd ed., 1996).

The local anesthetic is preferably selected from the group consisting ofbupivacaine, levo-bupivacaine, ropivacaine, levo-ropivacaine,tetracaine, etidocaine, levo-etidocaine, dextro-etidocaine, andlevo-mepivacaine.

Local anesthetics including, but not limited to, bupivacaine andropivacaine, which are related to aminoacyl local anesthetics exhibitintrinsic vasoactive effects on cerebral blood vessel tone and reducepain sensitivity locally. When administered dorsonasally, thesecompounds are believed to effect anesthesia of the SPG and other DnNSs,which results in increased volumetric flow of blood in cerebral bloodvessels and reduces inflammation initiated by functional ischemia. It isunderstood that the S(levo)-enantiomer of ropivacaine and theS(levo)-enantiomer of bupivacaine exhibit lower physiological toxicityand better sensory blocking properties than the correspondingR(dextro)-enantiomers. The S(levo)-enantiomer of ropivacaine ispreferred for use in the compositions and methods of the invention, asare the S(levo)-enantiomers of bupivacaine, etidocaine, and mepivacaine.

Ropivacaine exhibits lower cardiovascular and central nervous systemtoxicity than bupivacaine. Compared with bupivacaine, ropivacaine blocksnerve fibers, such as A(delta) and C sensory fibers, more preferentiallythan other neurons such as motor neurons (Rosenberg et al., 1986, Br. J.Anaesth. 55:163-167). Thus, ropivacaine is preferred over bupivacaine inthe compositions, kits, and methods of the invention.

For local anesthetics which have a chiral center (e.g., bupivacaine andropivacaine), the local anesthetic may be a single optical isomer of thelocal anesthetic, a racemic mixture of the optical isomers, or someother mixture of optical isomers. By way of example, a 90:10, a 80:20, a75:25, a 70:30, or a 50:50 ratio, by weight or by molecule number, ofone optical isomer to the other may be used. There is clinical evidencethat mixtures of local anesthetics such as bupivacaine and ropivacaine,wherein about 10-25% of the anesthetic is present in the dextro-form canprovide anesthesia of longer duration, more pronounced anestheticeffect, or both.

When the local anesthetic is an alkyl- or aryl-2-piperidinecarboxamidederivative such as mepivacaine, bupivacaine, ropivacaine, or etidocaine,the carbon atom at position 2 of the piperidine ring is a chiral center,as indicated with an asterisk in formula (III), wherein R is ethyl,phenyl, or C₅-C₈ straight- or branched-chain alkyl, and R′ is2,6-dimethylphenyl, thiophene, or 2,5-dimethylthiophene.

For these local anesthetics, it is preferred by the inventor to use thelevo-enantiomer at this chiral center in the compositions, kits,apparatus, and methods of the invention.

Similarly, when the local anesthetic comprises a chiral center(indicated with an asterisk) having the structure of formula (IV), it isalso preferred that the levo-enantiomer at the chiral center be used inthe compositions, kits, and methods of the invention, wherein R and R′are as defined above and wherein either (i) each of R″ and R″′ is astraight-chain alkyl and R″ and R″′ have a total of 4 to 6 carbon atoms,or (ii) R″ and R″′ together form a heteroalkyl ring having a total of 5to 7 carbon atoms and a nitrogen atom.

By way of example, etidocaine and prilocalne each comprise a chiralcenter within the definition of the structure of formula (IV), buthaving different R-groups.

It is understood by the inventor that the potency of anesthesia effectedby local administration of an aryl-2-piperidinecarboxamide derivativesuch as bupivacaine, ropivacaine, or lidocaine may be increased byincreasing the lipid solubility of the derivative. This may be achieved,for example, by increasing the lipophilic character of substituent ofthe piperidyl nitrogen atom. The partition coefficient of ropivacaine(in an n-heptane/buffer biphasic system) is about 2.9 times greater thanthe partition coefficient of lidocaine (Rosenberg et al., 1986, Br. J.Anaesth. 58:310-314). The partition coefficient of bupivacaine is about10 times greater than the partition coefficient of lidocaine (Id.). Asdescribed herein, ropivacaine and bupivacaine are long-acting localanesthetics, while lidocaine is not a long-acting local anesthetic.Thus, a way in which a skilled artisan may determine whether aparticular local anesthetic is a long-acting local anesthetic is todetermine whether the partition coefficient of the local anesthetic inan n-heptane/aqueous biphasic system is greater than the partitioncoefficient of lidocaine in such a system. If the partition coefficientof the particular local anesthetic is greater than the partitioncoefficient of lidocaine, then the particular local anesthetic is likelya long-acting local anesthetic. Preferably, the partition coefficient ofthe particular local anesthetic is at least 2.9 times greater than thepartition coefficient of lidocaine. The potency of anesthesia of a localanesthetic may be increased by modifying the chemical structure of thelocal anesthetic in such a manner as to increase the partitioncoefficient of the local anesthetic, for example by adding hydrophobicsubstituents to the local anesthetic molecule or lengthening hydrophobicsubstituents of the local anesthetic. Preferably, the local anestheticused in the compositions, kits, and methods of the present invention hasa partition coefficient in an n-heptane/aqueous biphasic system greaterthan the partition coefficient of lidocaine in such a system.

It is understood by the inventor that the duration of anesthesiaeffected by local administration of an anesthetic such as anaryl-2-piperadinecarboxamide derivative is related to the proportion ofthe anesthetic which is bound to protein in vivo. Approximately 95% ofeach of bupivacaine and ropivacaine is bound to protein in vivo, whileonly about 65% of lidocaine is bound to protein in vivo. Thus, anotherway in which a skilled artisan may determine whether a particular localanesthetic is a long-acting local anesthetic is to determine whether theproportion of the particular local anesthetic which is bound to proteinin vivo is greater than the proportion of lidocaine which is bound toprotein in vivo. If the proportion of the particular local anestheticwhich is bound to protein in vivo is greater than the proportion oflidocaine which is bound to protein in vivo, then the particular localanesthetic is likely a long-acting local anesthetic. The proportion ofthe local anesthetic used in the compositions, kits, and methods of thepresent invention which is bound to protein in vivo should be greaterthan about 65%. Preferably, the proportion of the particular localanesthetic which is bound to protein in vivo is at least about 95%.

The duration of anesthesia of a local anesthetic may be increased bymodifying the chemical structure of the local anesthetic in such amanner as to increase the proportion of the particular local anestheticwhich is bound to protein in vivo, for example by adding chemicalsubstituents to the particular local anesthetic molecule which arecapable of binding, covalently or non-covalently, to protein moieties.

The therapeutic effects of local anesthetics in the present inventionare not directly proportional to their prior art use elsewhere in thebody as local anesthetics. Thus, the duration and pain-relieving effectsof the long-acting and persistent local anesthetics in the presentinvention are enhanced, compared to their use as local anestheticselsewhere in the body. The enhanced duration and pain-relieving effectsof the long-acting and persistent local anesthetics of the presentinvention are surprising, compared with the effects achieved using othermethods of using local anesthetics.

For example, administration of ropivacaine may anesthetize a nervestructure for a period about 1.5 to about 4 times that achieved byadministration of lidocaine, depending on the location and type of thenerve structure, and further depending on the concentration and totaldose of the local anesthetic and on the presence of vasoconstrictors orother drugs which affect either uptake of the local anesthetic by thenerve structure or clearance of the local anesthetic from the anatomicalsite of the nerve structure. The difference between the period ofanesthesia effected by administration of ropivacaine and the period ofanesthesia effected by administration of lidocaine is less pronouncedwhen the site of administration is a skin or mucosal surface. Thus, onewould expect that if lidocaine and ropivacaine affected CNvDs and theirsymptoms by the same mechanism, administration of ropivacaine to apatient afflicted with a CNvD would provide relief lasting no more thanabout 4 times as long as the relief provided by administration oflidocaine, and probably closer to no more than about 1.5 times as long.In fact, as described herein, the relief provided by administration ofropivacaine to CNvD patients, such as migraine patients, persisted farlonger than the duration of relief provided by administration oflidocaine to such patients. This surprising result further highlightsthe difference between prior art methods of relieving a symptom of aCNvD and the methods of the invention for inhibiting a CNvD.

The use of microdroplets comprising a general anesthetic to effect localanesthesia are known and have been described, for example in U.S. Pat.No. 4,622,219. Liposomal preparations of local anesthetics are alsoknown and have been described, for example in U.S. Pat. No. 4,937,078.However, neither the use of a general anesthetic in microdroplet formnor the use of a sustained release preparation of one or more localanesthetics has been described prior to the present disclosure for thepurpose of inhibiting, or otherwise treating an acute CNvD or for thepurpose of reducing the severity of an acute cerebral ischemic event ina human patient. The preparations and uses of general anesthetics inmicrodroplet form and the preparations and uses of liposomalpreparations of one or more local anesthetics are included within thecompositions, kits, apparatus, and methods of the invention. Generalanesthetics which can be used in microdroplet form include, but are notlimited to, desflurane, diazepam, enflurane, etomidate, halothane,isoflurane, methohexital sodium, methoxyflurane, midazolamhydrochloride, propofol, sevoflurane, and thiopental sodium.

Dosing Information

The following dosing information is believed to be useful for theCNvD-inhibiting methods and the muscular headache-inhibiting methods ofthe invention. Dosing information relevant to the systemic drug deliverymethod of the invention is described separately in the portion of thepresent disclosure which describes that method.

Various dosage forms may be made which comprise a local anesthetic at aconcentration of about 0.01% to about 53% by weight, preferably aconcentration of about 0.25% to about 10% by weight, more preferablyabout 0.5% to about 5% by weight, and even more preferably at about 2.5%by weight. The pharmaceutical composition should be formulated todeliver about 10 micrograms to about 2.5 grams of the local anestheticto each nostril of a patient, and preferably to deliver about 10micrograms to about 1 gram. Unit dosage forms containing an amount ofthe pharmaceutical composition in these ranges may be used. When thepharmaceutical composition is in the form of a liquid for topicalapplication (e.g., a spray), a dose of the pharmaceutical compositionmay be contained, for example in a volume of about 0.5 milliliters toabout 5 milliliters, and preferably in a volume of about 1 milliliter toabout 3 milliliters, for delivery to each nostril. Such liquidpharmaceutical compositions preferably contain the local anesthetic at aconcentration of about 0.01% to about 20% (w/v), more preferably about0.25% to about 5% (w/v). When the pharmaceutical composition is in theform of a solid, semi-solid, gel, foam, mousse, creme, emulsion, or thelike, the pharmaceutical composition may be formulated to contain about10 micrograms to about 2.5 grams of the local anesthetic to the patientper nostril in a volume of about 0.5 milliliters to about the capacityof the nasal cavity. In one embodiment, the local anesthetic isdorsonasally administered in a total amount from about 1 milligram toabout 70 milligrams (although this amount may alternatively beadministered to each nostril), and preferably in an amount from about 10micrograms to about 50 milligrams. The concentration of the localanesthetic in the solid, semi-solid, gel, foam, mousse, creme, oremulsion form is preferably about 0.1% to about 53% (w/w), morepreferably about 0.2% to about 20% (w/w).

A bulk form of a long-acting local anesthetic pharmaceutical compositionmay be made and administered to a patient in one or more doses whichcomprise the dosage amounts described in the preceding paragraph.

Pharmaceutical Compositions

The long-acting local anesthetic pharmaceutical composition that isuseful in the methods of the invention may be intranasally ordorsonasally administered in a variety of formulations that can be madereadily by one of skill in the art of pharmacology in view of thepresent disclosure. Formulations which are useful for intranasaladministration of the pharmaceutical composition of the inventioninclude, but are not limited to, jelly, creme, gel, foam, mousse,semi-solid, emulsion, sol-gel, foam, a eutectic mixture, liquid,droplet, aerosol, powder, microsomes, liposome, sustained release,degradable polymer, polymer microspheres, impregnated film, fiber, orpatch, coated film, fiber, or patch, and other similar dosage forms. Thepharmaceutical composition of the invention may contain one or more thanone local anesthetic agent. When the pharmaceutical composition containsmore than one local anesthetic agent, the agents may be mixed insubstantially any ratio such as, for example, a eutectic ratio asdescribed in U.S. Pat. No. 4,562,060. Eutectic mixtures of localanesthetics can be rapidly and more easily taken up by submucosalstructures such as nerves, and thus are useful for submucosal nerveblock. In addition, levo local anesthetics are vasoconstrictors.Eutectic mixtures of a local anesthetic with a vasoconstricting agent(e.g., a levo local anesthetic) can exhibit prolonged local anestheticactivity and reduced systemic uptake relative to non-eutectic mixturesof the same local anesthetic.

In addition to the local anesthetic, such pharmaceutical compositionsmay contain pharmaceutically acceptable carriers and other ingredientsknown to enhance and facilitate drug administration with the additionalpharmaceutical agents disclosed herein. Compounds, formulations, anddosages of the additional pharmaceutically active agents described inthis method are known in the art. Owing, in part, to the vasodilatoryactivity of local anesthetics, these compounds may be used according tothis method at doses of about half their art-recognized doses to theirfull art-recognized doses.

Such pharmaceutical compositions may also contain ingredients to enhancesensory acceptability of the composition to a human patient, such asaromatic, aromatherapeutic, or pleasant-tasting substances. Thepharmaceutical compositions may also, for example, be made in the formof a flexible solid or semisolid carrier comprising the localanesthetic, such as one of the carriers described in U.S. Pat. No.5,332,576 or in U.S. Pat. No. 5,234,957; or in the form of suspendedmicrospheres, such as those described in U.S. Pat. No. 5,227,165. Solidand semi-solid formulations of a shorter-acting, a long-acting, or apersistent local anesthetic are preferred in the compositions, methods,and kits of the inventions, because such preparations improve localanesthetic localization. In these forms, there is less dilution of thelocal anesthetic by body fluids and less transport of the localanesthetic to an unintended body location. Furthermore, it is believedthat these formulations will reduce or minimize unintended side effectssuch as disagreeable taste, oropharyngeal numbness, dysphasia, andcompromise of protective reflexes. In these formulations, a lower amountof local anesthetic may be used, relative to other formulations.

Numerous pharmaceutically acceptable carriers are known in the art, asare methods of combining such carriers with local anesthetics. Examplesof such carriers and methods are described, for example, in Genaro, ed.,1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,Pa.

It is understood that the pharmaceutical composition of the inventionmay comprise a combination of any of the forms described herein. By wayof example, microparticles, microsomes, or liposomes comprising a localanesthetic may be suspended in a solution or other formulation of thesame or a different local anesthetic, whereby the solution or otherformulation provides a rapid onset of anesthesia and the localanesthetic in the form of microparticles, microsomes, or liposomesprovides a sustained duration of anesthesia. Sustained releasepreparations may comprise a slowly-released formulation of a localanesthetic. Inclusion of another local anesthetic in such formulations,in a free or salt (i.e., not slowly-released) form confers to theformulation the ability to act both with a rapid onset of anesthesia anda sustained duration of anesthesia. All such combinations offormulations described herein are included in the invention.

The long-acting local anesthetic pharmaceutical composition useful forpracticing the invention must be administered in a dose sufficient toinhibit the CNvD for at least about one hour, and preferably for atleast about two hours. Doses of the long-acting local anestheticpharmaceutical composition may be administered in a single dose, inmultiple doses, in sustained release doses, or continuously.

The local anesthetic(s) may be present in the pharmaceutical compositionat any concentration from a very dilute concentration through thesolubility limit of the local anesthetic in the medium in which it isdelivered. The local anesthetic(s) may also be present at aconcentration greater than the solubility limit of the local anestheticin the medium in which it is delivered by using a crystalline,microcrystalline, or amorphous solid form of the local anesthetic,preferably suspended in a gel, foam, mousse, creme, liquid, liposome,microsome, solid polymeric matrix, or the like. In various embodiments,the local anesthetic may be administered in the form of a eutecticmixture of local anesthetics, such as described in U.S. Pat. No.4,562,060, in the form of encapsulated or embedded local anesthetic,such as described in U.S. Pat. No. 5,085,868, in the form of anoil-in-water emulsion, such as described in U.S. Pat. No. 5,660,837, orin the form of an emulsion, a creme, a eutectic mixture, or amicroemulsion, such as described in International Patent ApplicationPublication No. WO 97/38675, particularly one having thermoreversiblegelling properties. Because the nasal cavity is normally cooler than gumpockets, the environment disclosed in International Patent ApplicationPublication No. WO 97/38675, a composition having thermoreversiblegelling properties, wherein the composition is a fluid at about 20° C.and a gel or semi-solid at the temperature in the human nasal cavity(i.e., about 30-37° C.), is preferred. Any of these compositions may beconveniently delivered dorsonasally and, once so delivered, will beavailable where placed within the nasal cavity for a sustained periodafter administration and will spread or drip into other tissues to alesser degree than would a liquid composition. By using one of theseformulations, less of the active compound yields greater therapeuticresults and has significantly decreased side effects, such as local andsystemic toxicity, tongue and oropharyngeal numbness, discomfort, badtaste, dysphasia, and possible compromise of protective airway reflexes.

Other possible formulations may be made by of one of skill in the art ofpharmacology in view of this disclosure without departing from thespirit of the invention. See, for example, (Genaro, ed., 1985,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.)for a number of forms of typical pharmaceutical compositions that may beadapted readily to the present invention in view of this disclosure.

Co-Administration of a Local Anesthetic with Another Migraine orMuscular Headache Therapeutic Agent

Numerous pharmaceutically active agents are thought to exhibit theirlimited therapeutic activity by virtue of the ability of the agent tointeract with one or more receptors present on the surface of cerebralblood vessels or other structures. By way of example, migrainetherapeutic agents known as serotonin receptor agonists include suchagents as sumatriptan and zolmitriptan, and are believed to interactwith serotonin receptors. In order to exhibit their pharmacologicaleffects, such agents must gain access by systemic vascular delivery tocerebral blood vessels which have altered vascular flow during an acutemigraine episode (Scott, 1994, Clin. Pharmacokinet. 27:337-344) and mustachieve a critical concentration at the cerebrovascular location of thecorresponding receptor(s) in the compromised area. Thus, thesepharmaceutically active agents must be administered at the onset of anacute migraine episode in order to avoid the cascade of inflammationthat follows initiation of the episode (Limmroth et al., 1996, Curr.Opin. Neurol. 9:206-210). Following delivery of one of these agents tothe compromised area of a cerebral blood vessel, the concentration ofthe drug gradually decreases at those sites, and rebound can occur.

Topical local anesthetics are vasodilators and therefore inhibitvasoconstriction, with the exceptions of cocaine, which is avasoconstrictor. It is believed that the vasodilatory effects of topicallocal anesthetic administration results from both a direct effect of theanesthetic upon the affected blood vessel and from an indirect effect ofthe anesthetic upon nerve structures associated with the blood vessel.

In normal states, most blood vessels, particularly those of smallerdiameter, do not transport blood because they are not open, due toconstriction of blood vessels located proximal thereto with respect tothe heart or due to increased muscle tone in the blood vessel wallitself. Should these vessels open at once, profound hypotension woulddevelop immediately, resulting in shock. Many and complex mechanisms areinvolved in the regulation of blood vessel tone and blood circulation.Hence, in any given tissue or organ, many blood vessels are closed.Blood vessel recruitment refers to a process whereby closed or partiallyconstricted blood vessels are opened or dilated. This increases thenumber and surface area of blood vessels available for uptake and allowsgreater blood flow through these vessels. The latter mechanism increasesdrug transport away, and this decreases local blood drug concentration,favoring drug diffusion into the blood. All of these mechanisms increasedrug uptake and transport. Surface vasodilation effected by anintranasally or dorsonasally administered local anesthetic other thancocaine promotes greater blood vessel recruitment and therefore, greatersystemic uptake of the pharmaceutically active agent administered inconjunction with the local anesthetic. Hence, co-administration of alocal anesthetic and a pharmaceutically active agent results in a morerapid and greater systemic uptake of the pharmaceutically active agent.This produces a more rapid and greater concentration of thepharmaceutically active agent at the affected site.

Furthermore, vasodilation of arterial structures which pass through theintranasal mucosa to feed other relevant neural structures will resultin increased delivery of intranasally administered pharmaceuticallyactive agents directly to target sites, especially if arterial bloodflows through an area to which the agent and anesthetic areadministered. For example, the sphenopalatine artery provides bloodsupply to much of the middle turbinate of the human nose, to the regionof the nasal epithelium overlying the SPG, and to the SPG. Withoutwishing to be bound by any particular theory, it is believed that theanesthetizing effect of local anesthetics such as bupivacaine inducesvasodilation of arterial structures coursing through local tissue on theway to the brain and other relevant neural structures, and increasesagent delivery. Additionally, the decreased extracranial andintracranial vasospasm and vasodilation which result from anesthesia ofthe SPG increases blood flow to relevant structures and thereforeincreases drug delivery to relevant tissues even further. Hence,intranasal administration of local anesthetic(s) induces both local andintracranial vasodilation and decreases or prevents vasoconstrictioncaused by normal autoregulatory processes, by neurally mediatedprocesses, or by release of neurotransmitters, neuropeptides, or otherfactors which are associated with an acute CNvD or muscular headache.Thus, administration of a local anesthetic to the region of the nasalepithelium overlying the SPG and to other regions of the epitheliumlocated nearby facilitates transport of a pharmaceutically active agentfrom the surface of the nasal epithelium directly into relevant venous,capillary, and arterial vessels and into the general systemiccirculation where intracranial vasodilation or decreased vasospasmresults in increased active agent delivery to sites at which it exhibitsits pharmaceutical activity.

Therefore, it is anticipated that dorsonasal delivery of a compositionwhich comprises a long-acting or persistent local anesthetic and apharmaceutically active agent will result in greater local delivery ofthe agent to a cerebral neurovascular tissue than could be achieved bydorsonasal delivery of the agent alone.

Furthermore, if agents, such as sumatriptan and ropivacaine, forexample, are believed to have different mechanisms of action, it isbelieved that the therapeutic effects of the two compounds will bepharmacodynamically synergistic, or at least additive. This is yetanother manner that co-administration of a local anesthetic and anotherpharmaceutical agent is advantageous.

Without wishing to be bound by any particular theory of operation, it isbelieved that the co-administered compositions inhibit the headache anddiminish the likelihood that the headache will rebound or recur. This isbelieved to be especially true for patients who are afflicted with aplurality of distinct headaches or patients who experience separateheadache triggers in series.

The present invention includes a method of inhibiting a neurovascular ormuscular headache in a human patient, the method comprisingintranasally, and preferably dorsonasally, administering to the patienta composition comprising at least one local anesthetic and apharmaceutically active agent effective for treatment of the headache.Preferably, the local anesthetic is a long-acting local anesthetic, apersistent local anesthetic, or a sustained release formulation of alocal anesthetic other than cocaine, whereby intranasal, and preferablydorsonasal, administration of the composition results in improved uptakeof the pharmaceutically active agent by a cerebral neurovascular tissueof the patient and to enhancement of the pharmaceutical activity of theagent.

By way of example, when the headache is a migraine, compositions forinhibiting the migraine and co-administering a migraine therapeuticagent include a sustained release formulation of a compositioncomprising sumatriptan (e.g., IMITREX™, Glaxo-Wellcome Inc., ResearchTriangle, N.C.) and lidocaine, a composition comprising zolmitriptan(e.g., ZOMIG™, Zeneca Pharmaceuticals, Wilmington, Del.) andbupivacaine, a composition comprising rizatriptan (e.g., MAXALT™, Merck& Co., West Point, Pa.) and ropivacaine, a composition comprisingnaratriptan (e.g., NARAMIG™, Glaxo-Wellcome Inc., Research Triangle,N.C.) and tetracaine, and a composition comprising a beta blocker andetidocaine.

Further by way of example, when the headache is a muscular headache,compositions for inhibiting the muscular headache and co-administering amuscular headache therapeutic agent include compositions comprising alocal anesthetic ingredient selected from the group consisting of apersistent local anesthetic, a long-acting local anesthetic, and asustained release formulation of a local anesthetic and an additionalpharmaceutically active agent selected from the group consisting of avasoconstrictor, epinephrine, norepinephrine, phenylephrine,methysergide, propanolol, a calcium channel blocker, verapamil, ergot,an ergotamine preparation, dihydroergotamine, a serotonin agonist,sumatriptan, zolmitriptan, rizatriptan, naratriptan, a chroman compound,aspirin, acetaminophen, a non-steroidal anti-inflammatory drug,caffeine, a narcotic, butorphanol tartrate, meperidine, a mast celldegranulation inhibitor, cromolyn sodium, eucalyptol, tetrodotoxin,desoxytetrodotoxin, saxitoxin, an organic acid, a sulfite salt, an acidsalt, a glucocorticoid compound, a steroid ester, magnesium or lithiumions, a centrally-acting analgesic, a beta blocker, an agent thatincreases cerebral levels of gamma-aminobutyric acid, butalbital, abenzodiazepine, valproat, gabapentin, divalproex sodium, a tri-cyclicantidepressant, a narcotic analgesic, an oral muscle relaxant, atranquilizer, a muscle relaxant, and another compound.

The local anesthetic compounds, formulations, dosages, and methods ofadministration which are useful for this method of the invention aresubstantially the same as those described herein with respect toinhibiting a neurovascular headache, a muscular headache, or a CNvD.Compounds, formulations, and dosages of the other pharmaceuticallyactive agents described in this method are known in the art. Owing, inpart, to the vasodilatory activity of local anesthetics, these compoundsmay be used according to this method at doses of about half theirart-recognized doses to their full art-recognized doses.

The composition may comprise a local anesthetic and a pharmaceuticallyactive agent which is effective for treating a CNvD or a muscularheadache. By way of example, such a composition may comprise ropivacaineand an additional ingredient. The additional ingredient may, forexample, be a serotonin receptor agonist, including, but not limited to,a triptan, e.g., sumatriptan or a chroman compound such as one of thecompounds described in U.S. Pat. Nos. 5,387,587; 5,420,151; 5,639,772;and 5,656,657, a non-steroidal anti-inflammatory drug, an anti-emetic,or a mast cell degranulation inhibitor such as cromolyn sodium.

In addition, the composition may comprise an agent which increases orprolongs either or both of the anesthetic effect and the tissue uptakeof the local anesthetic. Such agents include, for example, ann-glycofurol compound, such as one of the compounds described in U.S.Pat. No. 5,428,006, eucalyptol, a toxin such as tetrodotoxin,desoxytetrodotoxin, or saxitoxin, an organic acid, a sulfite salt, anacid salt, magnesium or lithium ions, and a centrally-acting analgesic.

In addition, the composition may be a combination of a beta blocker anda local anesthetic, as described, for example, in European Patent No.754060. The agent may also be a drug that increases cerebral levels ofgamma-aminobutyric acid (GABA), either by increasing GABA synthesis ordecreasing GABA breakdown. Such GABA-affecting agents include, forexample, butalbital, benzodiazepines, valproat, gabapentin, anddivalproex sodium. The agent may also be an agent effective fortreatment or prevention of neurodegenerative disorders such as, forexample, (S)-alpha-phenyl-2-pyridineethanamine (S)-malate, as describedin European Patent No. 970813. Furthermore, the agent may be a compoundwhich decreases inflammation, including, for example, a glucocorticoidcompound such as a steroid ester. Compounds, formulations, and dosagesof vasoconstrictors and other pharmaceutically active agents describedin this method are known in the art. Owing, in part, to the vasodilatoryactivity of local anesthetics, each of these compounds may be usedaccording to this method at doses of about half their art-recognizeddoses to their full art-recognized doses.

In a patient refractory to monotherapy or treatment using a localanesthetic composition comprising only one additional compound, thecomposition may be combined with one, two, or more additional compounds,and this combined composition may prove to have therapeutic effectswhich are synergistic, or at least additive, with respect to each of theindividual ingredients. By way of example, such a combined compositionmay comprise a long-acting or persistent local anesthetic, abeta-blocker, and a serotonin receptor agonist. Other examples include acombined composition comprising a long-acting or persistent localanesthetic and an anti-epileptic compounds such as phenyloin sodium(e.g., Dilantin®, Parke-Davis, Morris Plains, N.J.), a combinedcomposition comprising a long-acting or persistent local anesthetic anda serotonin receptor agonist, a serotonin subclass 5HT1F receptoragonist, LY334,370, and a combined composition comprising a long-actingor persistent local anesthetic and a sesquiterpene lactone (e.g., acompound such as parthanolide, obtained from an herb such as feverfew{Tanacetum parthenium}).

Methods of Effecting Intranasal or Dorsonasal Administration

Intranasal administration of a composition may be effected by any methodby which the composition is provided to any portion of the nasalepithelium. Intranasal administration of a composition comprising alocal anesthetic according to certain methods of the invention ispreferably effected by dorsonasal administration of the localanesthetic.

Dorsonasal administration of a pharmaceutical composition may beeffected by any method or route which results in delivery of thecomposition to a tissue, fluid, or surface of a human, whereby acomponent of the composition is provided to a DnNS either directly or bydiffusion through tissue or fluid interposed between the DnNS and thesite of administration. For example, dorsonasal administration of acomposition comprising a local anesthetic may be effected by injecting acomposition directly into a DnNS or by topically applying thecomposition to a tissue located in close anatomic proximity to the SPG,whereby the local anesthetic is capable of diffusing from the tissue toa DnNS such as the SPG. Topical dorsonasal administration may beaccomplished by an intranasal route or by an oropharyngeal route, forexample. As described herein, nasal drip methods, nasal sprayapplication methods, and mechanical application methods may be used toeffect topical dorsonasal administration of a composition comprising alocal anesthetic.

Intranasal administration of the composition of the invention may beimproved if the nasal cavity is rinsed, treated with a decongestant, orotherwise cleared of material which might impede intranasal deliveryprior to administration of the composition.

As described herein in Example 1, dorsonasal administration ofropivacaine to patients afflicted with migraine using an intranasalspray method, an intranasal drip method, or an intranasal cotton swabmethod yielded different response rates and different values for theefficacy of ropivacaine for relief of migraine. Although drip and spraymethods resulted in wider ropivacaine distribution within the nasalcavity, direct application of ropivacaine to the region of the nasalepithelium overlying the SPG using a cotton swab yielded the most rapidand most effective inhibition of migraine.

The pharmaceutical composition that is useful in the methods of theinvention may be administered topically in the types of formulationsnoted herein. Intranasal, and preferably dorsonasal, administration ofthe composition may be achieved by providing a mist or aerosol spraycomprising the composition to the nasal cavity via the nostril, byproviding drops or a stream of liquid comprising the composition to thenasal cavity via the nostril or by injection of the liquid using ahypodermic needle which penetrates the facial skin of the patient, bydirectly applying the composition dorsonasally using a flexible oranatomically-shaped applicator inserted through the nose or mouth of thepatient, including an applicator or implant which is left in place overa period of time, by introducing into the nasal cavity a liquid, gel,semi-solid, powder, or foam comprising the composition, or by any othermeans known to one of skill in the art of pharmaceutical delivery inview of this disclosure.

Intranasal, and preferably dorsonasal, administration of apharmaceutical composition to a human has distinct advantages relativeto other routes of administration. By administering a compositionintranasally or dorsonasally, a high local concentration of thecomposition in a relevant neural structure, and possibly in the cerebralneurovasculature, may be achieved relative to the systemic concentrationof the composition. Local delivery is advantageous in situations inwhich systemic exposure to the composition is undesirable, eitherbecause the composition is metabolized systemically or because systemicexposure results in harmful symptoms. By way of example, systemicadministration of a local anesthetic such as bupivacaine is undesirablebecause bupivacaine is metabolized in the liver and because systemicadministration of a relatively large amount of bupivacaine is known tocause serious adverse effects.

Another advantage of intranasal or dorsonasal administration of acompound, at least where local cerebral neurovascular delivery isdesired, is that a lesser amount of drug may be administered than wouldbe necessary to administer via a different route. Absorption ofintranasally or dorsonasally delivered drug into cerebral neurovasculartissue enables the patient to avoid digestive or at least some hepaticdrug metabolism which could occur, for instance, if the drug wereadministered orally. Furthermore, intranasal or dorsonasal delivery of adrug requires less intensive intervention by a medical professional thansome other delivery methods, such as intravenous delivery.Self-medication by an intranasal or dorsonasal route is practical, asevidenced by the many nasal and pulmonary delivery devices and drugformulations which are commercially available.

DnNSs may not be directly accessible via the nasal cavity. However,because of the anatomic proximity of DnNSs to the nasal epithelium,anesthesia of a DnNS can be effected by topical administration of alocal anesthetic to the region of the nasal epithelium overlying the SPGor to the region of the nasal epithelium near that region. For example,within the nasal cavity, the SPG lies dorsal to the posterior tip of themiddle concha, and is covered by the nasal epithelium at a variabledepth of one to nine millimeters (Sluder, 1908, N.Y. State J. Med.27:8-13; Sluder, 1909, N.Y. State J. Med. 28:293-298). Thus, a compoundapplied to the surface of the nasal epithelium at or near the region ofthe nasal epithelium overlying the SPG, such as the surface of the nasalepithelium dorsal to the posterior tip of the middle concha can diffusethrough the epithelium and any intervening tissue or fluid to reach theSPG.

The SPG, which is sometimes designated the pterygopalatine ganglion, islocated in the pterygopalatine fossa of the human skull, close to thesphenopalatine foramen and close to the pterygoid canal. The SPG issituated below the maxillary nerve where the maxillary nerve crosses thepterygopalatine fossa. Although it is also connected functionally withthe facial nerve, the SPG is intimately related with the maxillarydivision of the trigeminal nerve and its branches. The parasympatheticroot of the SPG is formed by the nerve of the pterygoid canal, whichenters the SPG posteriorly. The fibers of the parasympathetic root ofthe SPG are believed to arise from a special lacrimatory nucleus in thelower part of the pons and run in the sensory root of the facial nerveand its greater petrosal branch before the latter unites with the deeppetrosal branch to form the nerve of the pterygoid canal. Thesympathetic root of the SPG is also incorporated in the nerve of thepterygoid canal. The fibers of the sympathetic root of the SPG arepostganglionic, arise in the superior cervical ganglion, and travel inthe internal carotid plexus and the deep petrosal nerve. The vidiannerve is located in close proximity to the SPG, and the efficacy oflocal anesthetics for inhibiting an acute CNvD may arise, in whole or inpart, from anesthesia of the vidian nerve or another DnNS located inclose anatomic proximity to the SPG. It is also known that thetrigeminal nerve has anatomical and functional relationship(s) tocervical nerve 2. Other DnNSs which are located in close anatomicproximity to the SPG include, but are not limited to, the cavernoussinus ganglion, the carotid sinus ganglion, numerous branches of themaxillary nerve, the ethmoidal nerve, and the ethmoidal ganglion.

The ability of a compound to diffuse from the surface of the nasalepithelium to a DnNS such as the SPG depends, of course, on the abilityof the compound to diffuse through bodily tissues and fluids. Thus,compounds to be delivered to a DnNS by topical application to the nasalepithelium are preferably diffusible through both aqueous solutions andlipids.

Local anesthetics which are related to the class of local anestheticsdesignated aminoacyl local anesthetics exhibit both suitable aqueoussolubility and suitable lipid solubility for use in the methods of theinvention. It is believed that such local anesthetics are able todiffuse into nerves in their neutral, uncharged state, and that suchlocal anesthetics assume their pharmacologically active, charged statewithin nerve cells.

In the case of delivery of a local anesthetic to a DnNS such as the SPGvia topical application of the anesthetic to the nasal epithelium, it ispreferable that the anesthetic be sufficiently diffusible through bodilytissues and fluids and have a sufficiently long half-life in vivo thatthe anesthetic is able to diffuse from the epithelium to the DnNS in anamount and for a duration sufficient to anesthetize the DnNS orotherwise inhibit the physiological processes that result in one or moresymptoms of the CNvD, such as a period on the order of at least aboutone hour, and preferably at least about two hours. On the other hand,the diffusivity through bodily tissues and fluids and the in vivohalf-life of the anesthetic must not be so high and long, respectively,that the anesthetic is delivered systemically in an amount sufficient tocause the adverse effects known to be associated with systemicadministration of local anesthetics (see, e.g., Physician's DeskReference®, Medical Economics Co., Inc., Montvale, N.J., 51st ed., 1997,pp. 424-427).

Apparatus for Intranasal or Dorsonasal Administration of a Composition

Particularly contemplated apparatus for intranasal or dorsonasaldelivery of a composition to a human patient according to the methods ofthe invention include, but are not limited to, an anatomically-shapedapplicator, a metered dose dispenser, a non-metered dose dispenser, asqueezable dispenser, a pump dispenser, a spray dispenser, a foamdispenser, a powder dispenser, an aerosol dispenser, a dispensercontaining a propellant, an inhalation dispenser, a patch comprising thecomposition, an implant comprising the composition, a soft pipette withan elastomeric bulb in fluid communication with a reservoir containingthe composition, a dropper for directing the composition past theconchae of the patient to an intranasal nerve structure (InNS, includinga DnNS, but not limited to DnNSs), or intranasal blood vessel (InBV), aswab having an absorbent portion impregnated with the composition, aswab having an anatomically-shaped portion comprising an absorbentportion impregnated with the composition, and a swab having a compressedabsorbent portion in fluid communication with a reservoir containing thecomposition. An anatomically-shaped applicator is one which has a shapewhich permits insertion of the applicator into the nose or mouth of ahuman and which enables contact of the composition delivered by theapplicator with the surface of the region of the nasal epitheliumoverlying the InNS or with a surface of the nasal epithelium near theregion of the nasal epithelium overlying the InNS (e.g., a DnNS such asthe SPG). It is preferred that the shape and/or materials of theapparatus be selected for comfortable insertion or application via anintranasal route. The apparatus preferably is adapted to contact eithera superior portion of the nasal epithelium or a portion of the nasalepithelium that overlies a DnNS.

Another embodiment of an apparatus for intranasal or dorsonasal deliveryof a pharmaceutical composition of the invention comprises a body havinga plurality of passages through which a composition may be delivered.The device may be designed so that the pharmaceutical composition of theinvention is delivered through each passage, the passages beingindividually or collectively connected to, for example, a plurality oforifices in an anatomically-shaped applicator whereby the orificesdirect delivery of the composition to a plurality of locations withinthe nasal cavity when the applicator is inserted into the nose of apatient and operated. The device may alternately be designed so that thepharmaceutical composition of the invention is delivered through one ormore passages and an additional pharmaceutically active agent isdelivered through the same passages or through one or more differentpassages. Alternately, the device may comprise components of thepharmaceutical composition of the invention which are separatelydelivered through one or more passages of the device and mixed either ina passage of the device or in the nasal cavity of the patient.

Devices which contain, deliver, or produce a semi-solid long-actinglocal anesthetic composition are contemplated. To use one of thesedevices, an outlet of the device is situated in fluid communication withone of or both of the nostrils of a patient. A solid, foam, semi-solid,foam-forming fluid, or another fluid which exhibits an increase inviscosity upon administration, such as one of the type known in the art,is provided to the outlet, whereby it passes into the nostril of thepatient, filling or partially filling the nasal cavity. A localanesthetic in the composition contacts the walls of the nasal cavity,preferably in a dorsonasal location, and the local anesthetic is therebyadministered to the patient. The devices described herein can be used todeliver substantially any composition or material to the portion(s) ofthe nasal epithelium for which they are adapted.

Directed Intranasal Drug Delivery Devices

There are several known devices for effecting intranasal delivery of adrug or other non-gaseous pharmaceutically acceptable preparation. Suchdevices include, for example, liquid-containing squeeze bottles,liquid-containing pressurized containers, liquid-containing pump-typecontainers, droppers, microfine powder dispersers, and nebulizers.Although each of these prior art devices may be used to intranasallyadminister a pharmaceutical composition (e.g., according to any of themethods described herein), each of these devices has certain drawbacksand shortcomings which make their use for directed intranasaladministration of compositions (e.g., for dorsonasal administration)sub-optimal.

Liquid-containing squeeze bottles dispense atomized liquid uponpressurization of the bottle effected by squeezing. However, the amountof liquid expelled upon squeezing, the direction in which the liquid isexpelled, and the velocity at which it is expelled can vary quiteconsiderably based on how the user manipulates the device. Furthermore,the degree of atomization (i.e., the size of the droplets) may depend onthe force applied to the container.

Liquid-containing manual pump-type containers dispense atomized liquidupon actuation by the user of a pump mechanism, in which displacement ofa portion of the container along a vertical axis of the container causesatomized liquid to be expelled from a second portion of the container,generally in a direction parallel to the longitudinal axis of thecontainer. By inserting the second portion into a nostril and actuatingthe pump, a stream or mist of atomized liquid is expelled into thenostril. These devices, like the other prior art devices, exhibitsignificant variability in the direction in which the liquid isexpelled, owing to variation in the positioning of the device by theuser. Furthermore, because these devices are operated by applyingpressure to the device in a direction toward the interior of thenostril, these devices are uncomfortable and present the possibility ofinjury due to accidental excessive applied force or misplacement by thedistressed user.

Liquid-containing pressurized containers dispense atomized liquid uponmanipulation by the patient of a triggering mechanism. For example, manysuch devices comprise a valve through which atomized or liquidmedication is expelled upon depressing a trigger or other actuator toopen the valve. Although these containers may exhibit improved controlover the amount and velocity of expelled fluid, relative to squeezebottles, the intranasal direction in which the liquid is delivereddepends heavily on actions of the user.

Droppers, pipettes, and other bulk liquid instillation devices share thedrawback that either the patient must remain in an awkward position(e.g., lying on the back, with the head propped up and to one side) inorder to retain the liquid in the nasal cavity for an appreciable periodor, alternatively, that administration must be repeated numerous times,owing to rapid drainage of the liquid from the nasal cavity. Inaddition, instillation of bulk liquid into the nasal cavity presents therisk that the liquid will be inhaled by the patient into the lungs orpassed through the nasopharynx into the esophagus and digestive system.This increases uncomfortable numbness and potentially compromisesprotective airway and swallowing reflexes. Furthermore, increasedwastage leads to increased systemic levels of drug and decreased desiredlocal effects.

Microfine powder dispersers and nebulizers may be used to deliverpowders and atomized liquids, respectively, to the nasal epithelium, butshare a number of drawbacks. First of all, the pattern of delivery willlargely parallel the pattern of inhalative air flow through the nasalcavity, and therefore may not distribute the agent evenly to the nasalepithelium, particularly to more remote regions, such as the dorsonasalregion or a superior portion of the nasal epithelium. Second of all, asignificant portion of inhaled powder and mist bypasses the nasalepithelium altogether, and instead is carried, along with bulk inhaledair, into the bronchi and lungs. When systemic delivery of a compound isdesired, such bypass may be desirable. However, when local directedintranasal (e.g., dorsonasal) administration is desired, this bypass mayfrustrate effective delivery.

All of these prior art drug delivery devices share a common shortcoming.Each disperses the drug non-specifically to the nasal epithelium anddoes not target local areas such as those overlying a nerve structure(e.g., a portion of the nasal epithelium including or overlying a branchof an InNS such as the olfactory nerve or another DnNS such as the SPG,a ciliary blood vessel, or ciliary nerve), those overlying an intranasalblood vessel, or the nasal cavity orifices of the sinuses.

The shortcomings of the prior art drug delivery devices may beunderstood in view of the fact that directed administration ofcompositions to selected remote areas of the nasal epithelium (e.g., thedorsonasal region or a superior portion of the nasal epithelium) has notpreviously been demonstrated. Prior art intranasal drug delivery methodshave generally taught administration to the largest possible portion ofthe intranasal epithelium, in order to provide the drug to much of theintranasal epithelium. In contrast, as described herein, several of themethods of the invention teach that dorsonasal, or otherintranasally-targeted, administration of a pharmaceutical composition(e.g., a composition comprising a long-acting local anesthetic) may bepreferable for a number of reasons. For example, in one embodiment, themethod of inhibiting a cerebral neurovascular disorder described hereininvolves dorsonasally administering a long-acting local anestheticpharmaceutical composition to a human. Intranasal administration ofcompositions to portions of the nasal epithelium overlying an InNS or anInBV can deliver a pharmaceutically-active (i.e.,pharmacologically-active or biologically-active) agent to the InNS orInBV, or to another tissue that communicates therewith. For example,intranasal administration of a composition to a portion of the nasalepithelium overlying an InBV can be used to effect systemicadministration (or local vascular delivery) of the agent, and intranasaladministration of a composition to a portion of the nasal epitheliumoverlying an InNS can be used to effect delivery of the agent to anothernerve structure (e.g., a cephalic ganglion, the spinal cord, or aportion of the brain) with which the InNS connects.

First, it is believed that the site at which long-acting localanesthetics have their biological effect may be physically located at orin close proximity to the portion of the nasal epithelium to which anintranasally administered composition is applied (i.e., as describedelsewhere herein, for example, to the region of the nasal epitheliumoverlying the SPG for a dorsonasally administered local anesthetic);thus, dorsonasal administration may be preferable to general intranasaladministration because it directs the pharmaceutically active agent toor near its site of action for treatment of migraine and headache.

Second, site-directed (e.g., dorsonasal) administration may be used tointentionally limit intranasal delivery of the biologically active agentto non-desired intranasal sites, thereby minimizing uptake of thebiologically active agent into the bloodstream. This may be particularlyimportant with biologically active agents (e.g., dextro-bupivacaine)which, at high bloodstream concentrations of the agent, have undesirableside-effects are used.

Third, because directed intranasal administration limits uptake of theadministered agent into the bloodstream, the agent may be delivered(e.g., to a dorsonasal nerve structure) more frequently and at a higherconcentration or greater amount than it could if it were administered ina more anatomically diffuse way. Therefore, high concentrations of theagent may be achieved in a tissue (e.g., the SPG, cerebro-spinal fluid,or a brain or other CNS structure) located at or in close proximity tothe dorsonasal epithelium. When the agent has a biological activitywhich decreases over time (e.g., a local anesthetic), administration ofa high local concentration of the agent may prolong the duration of theintended biological effect.

Fourth, with intranasal administration of a compound having anuncomfortable, but non-harmful, side-effect (e.g., numbness), it may bepreferable to limit the exposure to the compound to the type or theamount of tissue which exhibits the side effect by administering thecompound only, or preferentially, to a selected portion of the nasalepithelium (e.g., dorsonasally), thereby limiting the side-effect uponnon-targeted tissues.

Other advantages of directed intranasal administration, in contrast togeneral intranasal administration will also be understood by the skilledartisan in view of the present disclosure.

With reference to FIGS. 4A, 4B, and 4C, the invention includes anintranasal drug delivery device or applicator which comprises a body100, preferably a generally elongate body such as a swab or a tube,which has a shape which conforms to the shape of the nasal cavity andhas distal portion having a distal end 103. The distal portion of theelongate body may be inserted into the apex A of the nasal cavity, asillustrated in FIG. 4, without injuring the patient. The apex of thenasal cavity is the superior and posterior portion of the nasal cavitywhich lies posterior to the nasal septum and anterior to thesphenoethmoidal recess. The apex of the nasal cavity communicates witheach of the nostrils, and the inferior IC, middle MC, and superior nasalconchae SC are situated in the passage from each nostril N to the apex.The elongate body may be substantially rigid or flexible, and ispreferably flexible, in order to facilitate placement of the distalportion thereof in the apex of the nasal cavity.

When not inserted into the nasal cavity, the elongate body may have agenerally curved or angled shape, wherein the longitudinal axis of theelongate body is angled at the distal end, with respect to thelongitudinal axis at the proximal end. Preferably the angle defined bythe intersection of the longitudinal axis at the distal end and thelongitudinal axis at the proximal end is about 90 and about 170 degrees,more preferably about 110 and about 160 degrees or about 120 and about150 degrees. The elongate body may be flexible along its entire length,or it may comprise one or more flexible or hinged sections, whereby thelongitudinal axis of the distal end of the body may be deflected fromthe longitudinal axis at the proximal end.

In an alternative embodiment, the body is elongated, has an ovalcross-section, is substantially straight, and has a lumen extendingtherethrough from the proximal end to the distal end. When the body isinserted into the nasal cavity, the distal end of the body extends abovethe nasal conchae, and the outlet port (i.e., at the distal end of thelumen) is positioned on the body such that the composition expelled fromthe outlet port is directed within the nasal cavity toward a selectedsurface of the nasal cavity, thus effecting directed intranasaladministration of the composition. For example, the device can have oneor more outlet ports that are positioned on the device such that whenthe device is inserted into the apex of the nasal cavity, a compositioncan be delivered through the lumen of the device dorsonasally, to asuperior portion of the nasal epithelium, or both. The device canalternatively be used to direct administration of the composition to oneor more other portions of the nasal cavity.

The shape of the intranasal delivery device may be envisioned asfollows. It is preferably in the form of an elongate solid or hollowbody, such as a tube, a flattened rod, or the like, that may beenvisioned as lying on a plane surface. The body is bent or curved alongthe surface of the plane, either at one point, at several points alongits length, or over its entire length, such that the longitudinal axisof the elongate body is angled at the distal end, with respect to thelongitudinal axis at the proximal end, as described above. The bodythereafter has a shape which conforms to the shape of a human nasalcavity. Optionally, the body may be further curved, again at one point,a plurality of points, or along its entire length, such that the distalend of the body is angled at an oblique angle with respect to the planewhen the proximal end of the body is maintained in the plane.

One or more sections of the elongate body may be curved to facilitateinsertion of the body past the nasal conchae, or to conform the shape ofthe body to the shape of the nasal cavity, in order that the body mayrest more securely and comfortably in the nasal cavity after insertion.

With reference to FIGS. 4A-4K, the body 100, illustrated as thepreferred elongate body, may have one or more lumens 101 extending fromthe proximal end thereof to one or more outlet ports 102 extending fromthe lumen to the exterior of the elongate body. The elongate body mayhave a substantially circular cross-section, an oval or flattenedcircular cross-section, a rounded rectangular cross section, a squarecross-section, or substantially any other cross-sectional shape which isaccommodated by the nostrils and nasal cavity of a human. The elongatebody may have an indicium or indicia thereon or therein which indicateto the user the orientation of the distal end of the body with respectto the longitudinal axis of the body at the proximal end thereof.Alternatively, the proximal end of the body may have a curved portionhaving a fixed relationship with the distal end, whereby the orientationof the distal end of the body may be determined. Thus, a user candetermine the orientation of the distal end 103 of the body 100 when itis emplaced within the nasal cavity of a patient by observing theposition of the indicia 105 at the proximal end of the body. This mayassist proper placement of the distal end of the applicator in the apexof the nasal cavity of the patient.

The outlet ports 102 may be located at the distal end 103 of the body100 (i.e., as in FIGS. 4A and 4B), along the distal portion of the body(i.e., as in FIG. 4C), between the proximal and distal ends (i.e., as inFIG. 4D), or some combination thereof. Outlet ports may also be locatedsubstantially at one peripheral location relative to the elongate body(e.g., all on one side of a flattened elongate body), or they may beperipherally distributed around the perimeter of the body. The outletports may have any shape (e.g., round, square, a slit, etc.). One ormore of the outlet ports may also be situated on the elongate body suchthat it will be occluded when the elongate body is placed within thenasal cavity of a patient. The body 100 may comprise a plurality oflumens 101, wherein certain outlet ports 102 communicate with one lumen,while others communicate with another lumen. Using such a device, aplurality of compositions may be administered to different sites withinthe nasal cavity. By way of example, the body may have a first lumenwhich communicates with a first set of outlet ports for dorsonasallyadministering a first composition to a patient and a second lumen whichcommunicates with a second set of outlet ports for administering asecond composition specifically to the nasal conchae or to a superiorportion of the nasal epithelium. By administering the composition to oneor more highly vascularized portions of the nasal epithelium or to aportion of the nasal epithelium overlying an InBV, the composition maybe systemically administered to the patient.

The lumen(s) may be connected to a fluid-, gel-, or powder-containingreservoir, or a needle, probe, tube, or other elongate instrument 110may be threaded through the lumen and, optionally, extended out of anoutlet port 102. For example, the elongate instrument 110 can bemaintained in a compressed state within the body 100 of the deviceduring insertion of the device into a nostril, and can be expandedthereafter (e.g., upon engorgement with liquid agent provided, forexample by way of the lumen 101, as illustrated in FIG. 4M). In variousembodiments the elongate instrument may include a swab, rosette,balloon, etc. which is impregnated or coated with a pharmaceuticallyactive composition and which is extended or inflated from the lumenthrough the outlet port following placement of the distal end of theelongate body in the apex of the nasal cavity (i.e., as in FIGS. 4F, 4G,and 4H). Such an extendable or inflatable elongate instrument 110 mayoptionally be retractable or deflatable. When the elongate instrument110 is inflatable, it may be positioned on the device in such a way thatit deflects a portion of the device upon inflation, as illustrated inFIG. 4G. An elongate instrument 110 can be tapered, as illustrated inFIG. 4N, to facilitate comfortable and minimally traumatic removal ofthe device from the subject's nostril. The elongate instrument may alsobe a solid or hollow needle which is coated with or which facilitatesdelivery of a pharmaceutically active composition (e.g., a localanesthetic) to a tissue located near the distal end of the elongate body(or near an outlet port 102) after placement of that distal end 103 inthe apex of the nasal cavity. The hollow needle may be either sheathedor non-sheathed, and may, for example, either contain or communicatewith a reservoir which contains a pharmaceutically active composition.

In one embodiment of the device/applicator, the elongate body has anangled shape, as illustrated in FIGS. 4J and 4K, an oval cross section,and two lumens 101 extending longitudinally therethrough from theproximal end to each of a pair of outlet ports located on the distalportion thereof. The two outlet ports are located on opposite faces ofthe distal portion of the body. The body has a shape which conforms tothe shape of the nasal cavity on either side of the nasal septum.Therefore, this body may be inserted into either nostril of the patientin order to administer a composition dorsonasally to the patient.Furthermore, this embodiment of the applicator may further comprise aswitching mechanism which permits the patient to select one of the twolumens for delivery of the composition, depending on the nostril intowhich the device is to be inserted. The switching mechanism may beassociated with an excluder mechanism which blocks or inhibits insertionof the device into the non-selected nostril. Such an excluder mechanismmay, for example, be an arm which is located beside the patient's noseon the side of the selected nostril when the device is inserted into theselected nostril, but which contacts the selected nostril in the eventthe patient attempts to insert the device into the non-selected nostril.

In another embodiment of this applicator, the body has one or morefibers embedded therein or passing through a lumen extendingtherethrough, whereby each fiber is fixed to the distal portion of thebody and extends through the proximal end of the body. By pulling ortwisting on a fiber, the pulling or twisting force may be imparted tothe distal end of the body, thereby permitting the distal end to be“steered” to some degree by manipulation of the fiber(s).

A pharmaceutical composition may be delivered to a tissue (e.g., the SPGor a tissue overlying it) located near the distal end 103 of the body100 after placement of that distal end in the apex of the nasal cavityeither by providing the composition through a lumen 101 in the elongatebody, as described above, or by applying the composition directly usingthe body. A pharmaceutical composition can also be delivered to tissuesthat are near an outlet port 102 when the device is emplaced in thenasal cavity (e.g., to the superior surface of the nasal cavity and tothe upper face of the superior concha using the device shown in FIG.4D). The applicator portion of the elongate body may be dipped in,constructed of, impregnated with, or coated with a compositioncomprising the pharmaceutical composition. Furthermore, the applicatorportion may be in fluid communication (e.g., by way of a lumen 101extending within the body 100) with a reservoir containing thepharmaceutical composition, whereby the composition may be provided fromthe reservoir to the applicator portion. For example, in the embodimentof the applicator depicted in FIG. 4L, a reservoir 114 is attached (orattachable, e.g., via a collar 116) to the body 100 such that a lumen101 which extends through the body 100 places the contents of thereservoir 114 in fluid communication with an absorbent portion 112associated with (e.g., attached to, initially compressed within, orboth) the opposite end of the body 100. Thus, the contents of thereservoir 114 can be absorbed by the absorbent portion 112, for exampleupon inverting the device or upon squeezing the reservoir 114. Directcontact of the applicator portion of the elongate body and a portion ofthe nasal epithelium situated in the apex of the nasal cavity transfersthe composition from the body to the epithelium. The body may also beconstructed of, or have a portion comprising, an absorbent material 104.The distal end 103 of the body 100 is preferably smooth or rounded, andmay optionally have a smooth or rounded member 106 attached thereto.

Alternatively, at least the distal end of the elongate body may have alayer of a pharmaceutical composition situated between the body and aretractable or degradable sheath which covers it. The sheath may, forexample, be retracted by sliding the sheath proximally along theexterior of the elongate body, or by drawing the sheath into or througha lumen extending within the elongate body. Retraction or degradation ofthe sheath exposes the pharmaceutical composition, which may then beapplied directly to a selected portion of the nasal epithelium, such asa portion overlying the SPG or a portion that includes or overlies oneor more branches of the olfactory nerve or another InNS or an InBV. Thedegradable sheath may, for example, be made of a material which degradesshortly following contact with moisture. Thus, by inserting a bodyhaving an applicator portion covered with such a degradable sheath intothe apex of the nasal cavity of a patient, degradation of the sheath iseffected and causes the composition on the applicator portion to beexposed, whereupon it may be applied to a portion of the nasalepithelium.

The invention further includes a systemic drug delivery device which hasthe same construction as the intranasal delivery device of theinvention, except that the device has an applicator portion, which may,for example, be a portion on which the drug is present, a portion towhich the drug may be supplied, or a lumen through which the drug may besupplied. This applicator portion is preferably adapted for location inclose anatomic proximity to a highly vascularized portion of the nasalepithelium when the distal portion of the body of the device is in theapex of the nasal cavity. Such a device may, for example, have anabsorbent portion in which the drug is absorbed and which contacts oneor more of the nasal conchae when the device is placed in the nasalcavity. Alternatively, the device may have a lumen which communicateswith an outlet port which is situated on the device such that the portis opposite a desired anatomic site (e.g., a nasal concha or the nasalorifice of a sinus) when the device is placed in the nasal cavity.

The invention also includes an anatomically adapted intranasal deliverynozzle 200 which may be used as an applicator for providing a gel, foam,vaporized, aerosolized, or atomized liquid, or a dispersed powder ormicropowder to or near the apex of the nasal cavity, while preferablyminimizing delivery of the composition to other portions of the nasalcavity. One embodiment of such a nozzle is illustrated in FIGS. 5 and 6.The nozzle has a body having one or more delivery lumens 201, each ofwhich extends through the nozzle from the proximal end 210 thereof toone or more outlet ports 202 located on the distal portion 203 thereof.The nozzle has an exterior portion which is shaped as follows. Theexterior portion has a flattened portion 204 situated between theproximal end 210 and the distal portion 203 thereof for seating againstthe nasal septum. The exterior portion also has an anterior portion 206situated between the proximal end 210 and the distal portion 203 thereoffor seating against at least one portion of the nasal cartilage. Theexterior portion also has a posterior portion having one or moreindentations 208 situated between the proximal end 210 and the distalportion 203 thereof for seating against one or more of the nasalconchae. Each indention has a generally curved shape which conforms tothe shape of the corresponding nasal concha. For example, the exteriorportion may have a distal and a proximal indentation, the distalindentation being located nearer the distal end of the nozzle, whereinthe distal indentation is adapted to the shape of the middle concha forseating the nozzle against the middle concha, and wherein the proximalindentation is adapted to the shape of the inferior concha for seatingthe nozzle against the inferior concha.

The delivery lumen 201 of the anatomically adapted intranasal deliverynozzle extends from the proximal end 210 of the nozzle to a dischargeport 202 at the distal end 203 thereof. When the nozzle is seated in thenasal cavity of a human, the discharge port is situated such that theaxis extending (generally perpendicularly) through the discharge portpasses through the apex of the nasal cavity, or is offset from the apexof the nasal cavity by an angle, phi, as indicated in FIG. 6, such thatphi is from 0 to about 30 degrees, and preferably such that phi is from0 to about 15 degrees. The discharge port may be generally circular, orit may be shaped (e.g., oval, or circular having opposed raised portionson the circumference thereof) in order to more specifically direct thecomposition discharged therethrough at a selected portion of the nasalepithelium (e.g., a portion situated in the sphenoethmoidal recess). Theproximal end of the anatomically adapted dorsonasal delivery nozzle maybe connected with one or more reservoirs, generators, or other sourcesof the agent, or a combination of agents, to be delivered therethrough.A single source of agent may be directed through a plurality of deliverylumens which connect the source with one or a plurality of dischargeports. Alternatively, independent sources of different agents may bedirected through a plurality of delivery lumens which connect thesources with one or a plurality of discharge ports.

The anatomically adapted intranasal delivery nozzle may be constructedof a rigid, flexible, deformable, or elastomeric material. In oneembodiment, the nozzle is constructed of a material which is, eitherinitially or under certain conditions (e.g., above a certaintemperature), deformable. Such a material may, for example, be a wax ora plastic which becomes pliable when heated to a temperature abovenormal body temperature (i.e., >about 98° F.), but below a temperaturewhich will cause injury to human nasal epithelium upon contact therewithfor several minutes (i.e., <about 108° F.). Other exemplary materialsare plastic composition which either remains plastic (e.g., a closedcell foam) or are which hardens with time (e.g., a polymerizingplastic). According to this latter embodiment, the nozzle is insertedinto a nostril of the patient who will thereafter use the nozzle, inorder to conform the nozzle to the interior geometry of that patient'snasal cavity. This procedure is preferably performed by a medicalpractitioner, or by a person having knowledge of the anatomy of thehuman nasal cavity, so that the nozzle is seated in the patient'snostril such that the discharge outlet is directed toward the apex ofthe patient's nasal cavity (i.e., the angle phi in FIG. 6 is from 0 toabout 30 degrees). Alternatively, a deformable material may be insertedinto a patient's nasal cavity in order to record the shape thereof, andthis deformed material may subsequently be used to fashion a mold forduplicating that shape.

The anatomically adapted dorsonasal delivery nozzle may optionallyfurther comprise one or more distal seating portion which, uponinsertion of the nozzle into the nostril of the patient, contact thesuperior surface of the nasal cavity, thereby preventing over-insertionof the nozzle. The discharge port(s) may be inferiorly spaced withrespect to the distal seating portion when it is seated within the nasalcavity of the patient, so that the path between the discharge port andthe apex of the nasal cavity is not blocked by the conchae.

The anatomically adapted intranasal delivery nozzle is used to deliver acomposition intranasal by seating the nozzle in a nostril of a patient,such that the flattened portion is seated against the nasal septum, theindentation, if any, is seated against a concha, and the anteriorportion is seated against the nasal cartilage. Optionally, or in placeof one of these other seatings, the distal seating portion is seatedagainst the superior surface of the nasal cavity. When the nozzle isthus seated, a gel, foam, mousse, liquid, dispersed power, aerosol, etc.comprising the composition is provided to the delivery lumen, thence tothe discharge port, and thence into the nasal cavity of the patient(e.g., to a dorsonasal or superior portion of the nasal epithelium). Inthe apex, the composition can contact a dorsonasally located portion ofthe nasal epithelium and thereby deliver the composition to thatportion. It is noted that certain anatomically adapted intranasaldelivery nozzles may be adapted for only one nostril of the patient;when this is so, a second nozzle adapted for the other nostril of thesame patient should be provided. Alternatively, the outlet port of thenozzle may be changeable (i.e., rotatable or deflectable), such that thesame adapter portion, with the outlet port facing in the oppositedirection, may be used in the patient's other nostril.

The anatomically adapted delivery nozzle of the invention may beadapted, by placing the outlet port thereof at an alternative locationon the body of the nozzle, to deliver a composition specifically to adifferent portion of the nasal cavity, such as to the nasal cavityorifice of one or more sinuses. The composition thus delivered may, forexample, be a pharmaceutical composition comprising one or both of asteroid and a vasoconstrictor. By specifically delivering such acomposition to the anatomical site at which it exerts its biologicalactivity, the amount of drug which is administered may be minimized andside effects normally associated with administration of the composition(e.g., nasal epithelial hypertrophy associated with intranasaladministration of vasoconstrictors) may be minimized.

The invention also includes an intranasal drug delivery device orapplicator which overcomes a particular shortcoming of prior artintranasal drug delivery devices. As illustrated in FIG. 7A, prior artintranasal drug delivery devices are actuated by applying pressure toall or a portion of the applicator in a direction that is substantiallyco-linear (i.e., not more than about 15 degrees offset from co-linear)from the axis of the nostril. Use of such devices carries the risk thatthe device may be unintentionally urged, along the axis of the nostril,with excessive force, leading to discomfort or injury of the patient.

The improved intranasal drug delivery device 300 of the inventionovercomes this limitation by changing the direction in which pressure isapplied to the device by the patient. As illustrated in FIGS. 7B and 7C,the improved intranasal delivery device comprises an intranostrilapplicator 302 having a lumen extending therethrough. The lumen of theintranostril applicator is in fluid communication with a discharge porton an end of the intranostril applicator, which is insertable within anostril of a human patient. This lumen is also in actuatable fluidcommunication with a drug within a container 304. Fluid communicationbetween the lumen and the interior of the container is actuated byapplication of force by the patient to an actuator interposed betweenthe lumen and the interior of the container. When the patient appliesforce to the actuator, the drug is provided to the lumen of theintranostril applicator, thence through the discharge port and into thenasal cavity of the patient.

The intranostril applicator may be substantially any body which may beinserted fully or partially into the nostril of a human and which has alumen extending therethrough. The drug container may be substantiallyany container which is pressure-activated, such as a pressurized drugcontainer connected to the lumen of the intranostril applicator by amanual pressure-actuated valve, a pressure-activated pump, a syringe, ametered dose applicator, and the like. Preferably, the intranostrilapplicator and at least a portion of the drug container are of a unitaryconstruction. Alternatively, the intranostril applicator and the drugcontainer may be detachable, whereby the intranostril applicator may beinserted into a nostril of a patient prior to attaching the drugcontainer thereto.

An important feature of the improved intranasal drug delivery device ofthe invention is that the pressure which is applied by the patient inorder to actuate the same is applied at an angle offset from (i.e., atleast about 15 degrees offset from, and preferably about 30, about 45,about 60, or about 90 degrees offset from) the axis of the nostril inwhich the intranostril applicator is placed. The discomfort and the riskof injury to the patient due to inappropriate drug source actuationpressure is thereby reduced significantly, and the device is also madeeasier to use. Any inappropriate pressure is likely to cause theintranostril applicator to twist within or become disengaged from thenostril, rather than cause the intranostril applicator to be drivenalong the axis of the nostril into a tissue, which would injure thepatient.

The invention also includes a dorsonasally implanted electronic neuralstimulator, such as a transepithelial neural stimulation (TENS) device.This device is implanted anatomically close to, preferably in contactwith, a dorsonasal nerve structure such as the SPG. The device may, forexample, be implanted on or in the dorsonasal epithelium, such as aportion of the nasal epithelium overlying a dorsonasal nerve structure.The device may be mono- or bi-polar. The device may have an internalpower supply, or power may be supplied to the device using an externaldevice (e.g., an inductively coupled power supply). Nerve block of adorsonasal nerve structure may thus be effected by energizing thedevice, meaning that electrical potential is provided to the device,such as from an internal power supply, external power supply leads, orfrom an extra-corporeal inductively coupled power supply.

The Kit of the Invention

The invention additionally includes a kit comprising a long-acting localanesthetic pharmaceutical composition, as described herein, and anapplicator, as also described herein, for intranasally, and preferablydorsonasally, administering the composition to a human patient toinhibit a CNvD. The kit is used by administering the composition to thepatient at a time when the patient is experiencing a symptom of a CNvDepisode or a prodromal symptom of a CNvD. The kit may further comprise amigraine therapeutic pharmaceutical agent, another pharmaceuticallyactive agent, another local anesthetic, and the like. The kit may, andpreferably does, further comprise instructional material which describesdirected intranasal (e.g., dorsonasal) administration of the compositionto a patient. The instructional material may, for example, comprisewritten instructions to intranasally or dorsonasally administer thecomposition included in the kit in accordance with this invention.

The kit described herein may also be used for inhibition of muscularheadaches. The components of the kit for this purpose are substantiallythe same, with the exception that any instructional material shoulddescribe the usefulness of the compositions and methods of the inventionfor inhibiting a muscular headache, rather than, or in addition to, aCNvD. If the kit may also be used to inhibit a muscular headache, inwhich instance the local anesthetic pharmaceutical composition need notbe long-acting and is administered to the patient during a muscularheadache episode.

Co-Administration of a Local Anesthetic and Another Compound to EffectSystemic Delivery of the Compound

The invention further relates to the discovery that non-intravenousadministration of a composition comprising a local anesthetic and apharmaceutically active agent to an animal such as a mammal,particularly a human, improves systemic uptake of the agent in theanimal, relative to the uptake achieved by non-intravenousadministration of the agent alone to the animal by the same route.

The present invention includes a method of systemic drug delivery, themethod comprising non-intravenously administering to a human patient acomposition comprising a local anesthetic and a pharmaceutically activeagent, whereby systemic delivery of the agent is improved relative tosystemic delivery of the agent when delivered by the samenon-intravenous route in the absence of the local anesthetic. Thepharmaceutically active agent may be any drug. It is contemplated thatthis method of effecting systemic delivery is particularly useful fordelivery of any agent which is able to diffuse through vascular andother tissues to a greater degree in the presence of the localanesthetic than in the absence of the local anesthetic. Thus, the agentmay be, for example, a hormone, a peptide, a liposome, or a polymericmolecule such as heparin.

Any pharmaceutically active agent which is desired to be deliveredsystemically may be co-administered non-intravenously in a compositioncomprising the agent and a local anesthetic. Where the local anestheticis not being administered for the purpose of inhibiting a CNvD, deliveryof a composition comprising a local anesthetic and the agent intendedfor systemic delivery need not be directed to the dorsonasal region ofthe nasal cavity. Because the nasal cavity is highly vascularized,delivery of the composition may be directed to substantially any portionof the nasal epithelium to achieve systemic delivery of the agent.Furthermore, the composition may be delivered to any vascularizedtissue, such as to the surface of a mucosal epithelium or to a skinsurface, for example, to achieve systemic delivery of the agent.

The local anesthetic may be any local anesthetic except cocaine, whichis a vasoconstrictor. The local anesthetic compounds, formulations,dosages, and methods of administration which are useful for this methodof the invention are substantially the same as those described hereinwith respect to inhibiting a neurovascular headache, a muscularheadache, or a CNvD. Compounds, formulations, and dosages of the otherpharmaceutically active agents described in this method are known in theart. Owing, in part, to the vasodilatory activity of local anesthetics,these compounds may be used according to this method at doses of abouthalf their art-recognized doses to their full art-recognized doses.

Theory Proposed to Explain the Mechanism of Improved Systemic Deliveryof a Pharmaceutically Active Agent by Co-Administration with a LocalAnesthetic

Without wishing to be bound by any particular theory, it is believedthat administration of a local anesthetic to a vascularized tissueinduces dilation of blood vessels within the tissue. Vasodilationresults in recruitment of surface blood vessels and increases theability of a compound present in the tissue to pass into the systemiccirculation. Similarly, carrier preparations (e.g., DMSO, proteins,peptides, and/or charged compounds) can facilitate delivery of thecomposition to an InNS or InBV to effect systemic or CNS delivery of thecomposition. Therefore, co-administration to a tissue of a localanesthetic and a pharmaceutically active agent improves the ability ofthe agent to pass from the tissue to the bloodstream for systemicdelivery.

Dosing Information Relevant to Systemic Drug Delivery

The local anesthetic doses and formulations which are useful forco-administration of the local anesthetic and another compound to effectsystemic delivery of the compound are substantially the same as thosedescribed for the method of inhibiting a CNvD. In view of the presentdisclosure, it will be understood by the artisan of ordinary skill thatthe dose and formulation of the local anesthetic will depend upon, amongother factors, the age, size, condition, and state of health of theanimal, the anatomical location to which the composition will bedelivered, the identity of the local anesthetic, and the identity of thecompound to be co-administered. Substantially any amount of localanesthetic may be used. By way of example, compositions which comprisethe compound to be co-administered and the local anesthetic at aconcentration of about 0.01% to about 53% by weight, and preferablyabout 0.25% to about 10% by weight, more preferably about 0.5% to about5% by weight, and most preferably about 2.5% by weight, may be used. Thecomposition may be prepared as a liquid, a semi-solid, or a solid, asdescribed herein. The composition may be formulated for intranasal,topical, subcutaneous, buccal, or substantially any othernon-intravenous route of administration using methods and compositionswell known in the art. The dose of the compound to be co-administered isdependent upon the identity of the compound, the purpose for which thecompound is to be administered, and the size, age, condition, and stateof health of the animal. Compounds, formulations, and dosages ofpharmaceutically active agents described in this method are known in theart. Owing, in part, to the vasodilatory activity of local anesthetics,these compounds may be used according to this method at doses of abouthalf their art-recognized doses to their full art-recognized doses.

While the invention has been described with reference to human anatomy,it is contemplated that the compositions and methods of the inventioncan be used analogously in any animal, particularly in any mammal,especially regarding co-administration of a local anesthetic and anypharmaceutically active agent to effect or enhance systemic delivery ofthe agent.

Directed Intranasal Administration of a Pharmaceutical Composition

Intranasal administration of a pharmaceutical composition directed toonly a portion of the nasal epithelium of a patient can avoid drawbacksof previous non-directed intranasal delivery methods. For example,administration can be directed specifically to a portion of the nasalepithelium that overlies (or is in close proximity to) an InNS or anInBV. For compositions (e.g., local anesthetics and compoundsco-administered with a local anesthetic) that are capable of diffusingthrough epithelial tissue, directing administration to a portion of theepithelium located in close anatomical proximity to the InNS or InBV canresult in delivery of the composition to the selected InNS or InBV.

When delivery of a composition to the olfactory nerve (or thence to theolfactory bulb or the brain) is desired, the composition should beadministered to the superior surface of the nasal cavity, where thebranches of the olfactory nerve that penetrate the cribiform plate ofthe ethmoid bone and emerge at or near the surface of the nasalepithelium. At least some extensions of the olfactory nerve emerge fromthe ethmoid into the superior nasal concha and the upper portion of thenasal septum. The dorsonasal portion of the nasal epithelium can alsoinclude branches of the olfactory nerve, although innervation variesamong individuals. Directed intranasal delivery of a composition to anerve structure such as the olfactory nerve demonstrates that intranasaladministration of a composition, if directed to an appropriateintranasal tissue or structure, can result in uptake of an active agentby a nerve structure that is separated from the nasal cavity by a bone(e.g., the olfactory nerve is separated from the nasal cavity by thecribiform plate of the ethmoid bone as well as the nasal epithelium).

Portions of at least the olfactory, nasal, ethmoidal, palatine, greaterpetrosal, and maxillary nerves are located in close anatomical proximityto portions of the nasal epithelium, and compositions having asufficiently high ability to diffuse through nasal epithelium tissue canbe delivered to these nerves by way of intranasal administration to thecorresponding portion of the nasal epithelium.

The identity of the active agent in the composition administered to anInNS or an InBV is not critical, so long as the composition isadministered to a portion of the nasal epithelium overlying or insufficiently close proximity to the InNS or InBV and in a carrier orwith a compound (e.g., a local anesthetic, lipid carrier, or othertissue-penetrance-modulating preparation) that facilitates diffusion orother transport of the agent to the InNS or InBV. Non-limiting examplesof useful agents include natural or altered or carrier viruses, prions,other infectious or therapeutic cellular or subcellular agents ormicroorganisms, stem cells, or other cellular therapeutic agents, DNA,RNA, oligonucleotides, polypeptides, amino acids, fatty acids, lipids,carbohydrates, vitamins, supplements, minerals, nutrients, oxygenatedsubstrates, microspheres, antibiotics, antiviral agents, antifungalagents, memory enhancing agents, neurotransmitters, antiepileptics,antiseizure agents, analgesics, ions including magnesium,anti-neuropathic pain agents, anti-central pain agents, antidepressantagents, cox inhibitors (including cox2 inhibitors), LOX inhibitors,membrane stabilizing agents, growth factors, hormones (e.g., anabolicand catabolic steroids), ATP, ADP, NAD(P), NAD(P)H, energy substrates,propylene glycol, carrier molecules, DMSO, cytokines, anti-cytokines,TNF, anti-inflammatory agents, melatonin, chemotherapy agents, andradiolabeled compounds.

In one embodiment, intranasal delivery of a composition containing anactive agent is performed as described herein. The composition isadministered to a portion of the nasal epithelium that overlies an InNS.The composition is administered in a sufficiently high amount that theagent is not only taken up by the InNS, but is also delivered to anothernerve structure with which the InNS communicates. In one example, acomposition is administered to a superior portion of the nasal cavity inorder to effect delivery of an agent to the olfactory nerve. By way ofthe olfactory nerve, the agent travels (e.g., diffuses or is activelytransported) to the olfactory bulb of the brain (i.e., with which theolfactory nerve connects) and thence to the brain. In another example, acomposition comprising an agent is dorsonasally administered so that theagent is taken up by a DnNS (e.g., the SPG) and transported to anothernerve structure with which the DnNS is connected (e.g., the SPG isconnected to the trigeminal nerve and, by way thereof, to the brain). Inthis way, cephalic, spinal cord, or other neural delivery of the agentcan be effected. Similar methods can be used to direct administration ofthe composition to other portions of the nasal cavity so as to effectdelivery to selected InNSs, selected InBVs, and tissues in which the twoare intimately related.

The dose of agent that should be used in the intranasal delivery methodsdescribed herein depends on the identity of the agent and the identityof the targeted tissue. When compositions are directed to a portion ofthe nasal cavity including or overlying an InNS in order to effectdelivery of the composition (or a component of the composition) to thecentral nervous system (CNS), the dose of the agent in the compositioncan often be significantly lower than the dose that would be necessaryto administer by an oral or intravenous route. When systemic delivery ofan agent is desired, directed delivery of a composition comprising ahigh concentration of the agent can be used, so as to enhance the rateand amount of agent taken up into the bloodstream. Thus, agentsdelivered by directed intranasal administration can be administered inconcentrations and amounts ranging from at least several times theamount administered orally or intravenously to amounts as small as 1% to10% the amount administered orally or intravenously, depending on theagent. A skilled artisan is able to titrate amounts appropriately, forexample administering a small amount at first and gradually increasingthe dosage until a desired pharmacological effect is achieved.

The invention is now described with reference to the following Examples.These Examples are provided for the purpose of illustration only and theinvention should in no way be construed as being limited to theseExamples, but rather, should be construed to encompass any and allvariations which become evident as a result of the teaching providedherein.

EXAMPLE 1 Dorsonasal Administration of Ropivacaine for Inhibition ofAcute Migraine Episodes

The purpose of the experiments described in this Example was todetermine the efficacy of dorsonasal administration of ropivacaine forinhibition of acute migraine episodes. Ropivacaine was dorsonasallyadministered to individual patients experiencing head pain, othersymptoms, or both, believed to be associated with an acute migraineepisode. Patients assessed head pain prior to and after ropivacaineadministration.

Dorsonasally administered ropivacaine rapidly inhibited of migraine in92% of the ambulatory patients, as evidenced by an average 90% reductionin perceived pain within one hour, usually within 15 minutes or less.Symptoms of nausea and photophobia associated with acute migraineepisodes in patients were similarly inhibited. Rebound of migraineoccurred in only 5.4% of patients within twenty-four hours of treatment.These results demonstrate that dorsonasal administration of ropivacaineis an efficacious method of inhibiting an acute migraine episode.

The materials and methods used in the procedures performed in thisExample are now described.

Ropivacaine Composition

Ropivacaine-HCl (NAROPINT™, Astra USA, Westborough, Mass.) was used asthe commercially-available 0.75% (w/v) solution, and was obtained in 30milliliter, sterile injectable vials.

Methods of Ropivacaine Administration

Three methods were used to achieve dorsonasal delivery of ropivacaine toindividual patients. Ropivacaine was administered to a first group ofpatients by an intranasal drip method. Ropivacaine was administered to asecond group using cotton swabs, the absorbent portions of which weresaturated with the ropivacaine solution. Ropivacaine was administered topatients in a third group by spraying the ropivacaine solution into eachnostril, using either a squeeze-type spray bottle or a metered-dosespray bottle.

The intranasal drip method used to administer ropivacaine to the firstgroup of patients was a based on the method described by Barre (1982,Headache 22:69-73), except that the ropivacaine solution was used inplace of the solution used by Bane. Approximately 0.75 milliliter toapproximately 1.0 milliliter of the ropivacaine solution wasadministered by way of each of the nostrils of each patient.

The cotton swab method used to administer ropivacaine to the secondgroup of patients comprised gently inserting cotton swabs, sequentiallyand bilaterally, into the nostrils of patients and urging the swabsdorsally until their absorbent portions contacted portions of nasalepithelium located dorsal to the middle conchae. Each swab was left inplace for approximately one minute, and was then withdrawn.Approximately 0.5 milliliter of the ropivacaine solution was deliveredto each nostril using this method.

Patients in a third group were administered ropivacaine by spraying lessthan about 0.5 milliliter of the ropivacaine solution into each of thepatient's nostrils using either a sterile squeeze bottle or a sterilemetered-dose spray bottle of known design. The design and operation ofeach of these spray bottles are well known in the art.

Prior to administration of ropivacaine, each patient was placed in asupine position with the patient's head hyperextended approximately 45degrees and rotated approximately 30 degrees to the right side. In thisposition, an imaginary line extending from the region of the nasalepithelium overlying the SPG of the patient through the patient's leftnostril was approximately vertical. Ropivacaine was then administered tothe left nostril of the patient as described for each of the threegroups of patients. Ropivacaine was administered to each patient's rightnostril after rotating the patient's head approximately 30 degrees tothe left. Ropivacaine was administered to both nostrils of each patientto prevent cases of unilateral migraine from developing intocontralateral migraine.

Assessing Ropivacaine-Induced Pain Relief

Prior to ropivacaine administration, each patient rated perceivedheadache pain according to a standard pain scale of the type used in theart. Patients were asked to rank the severity of pain which they wereexperiencing on a scale from 0 (no pain) to 10 (worst pain imaginable).This ten-point pain rating scale is analogous to, but has moregradations than, the four-point rating system used by the InternationalHeadache Society (IHS; Headache Classification Committee of theInternational Headache Society, 1988, Cephalalgia 8 (Suppl. 7):19-28).Ropivacaine was administered to one nostril of each patient, and then tothe other. The time required to administer ropivacaine to both nostrilsof each patient was approximately three minutes. Five minutes after thecompletion of administration of ropivacaine to the patient's firstnostril, each patient again rated perceived headache pain. If no painrelief was evident, dosing was repeated, and the rating procedure wasrepeated. Pain ratings were obtained for each patient until peak effectappeared to be achieved, for up to ninety minutes, acutely. Follow-up ofeach patient's condition was attempted by direct contact or by telephonecontact between six and eight hours post-treatment, between twenty-fourand forty-eight hours post-treatment, and up to one week post-treatment.

The results obtained from the procedures performed in this Example arenow described.

The population of patients treated in the procedures performed in thisExample comprised forty-two adults, each of whom sought migraine relief.The results of treatment of each of these patients with eitherropivacaine or (for three patients) lidocaine are presented in Table 1.The five patients who were either treated with lidocaine or did notclearly meet the IHS criteria for migraine were not included in theanalysis presented herein of the efficacy of dorsonasal ropivacainetreatment of migraine. The demographic and pretreatment characteristicsof the patients who met IHS migraine criteria and who were treated withropivacaine are presented in Table 2.

TABLE 1 Summary of Patient Data. Patient Medical Headache AssociatedIdentifier History¹ History² Symptoms³ Treatment⁴ Results⁵ P#1 PosteriorMild Nausea R 0.75% Initial pain: 8 Migraine Photophobia 2 Sprays Pain10 min post-treatment: 0 No rebound up to 24 hours P#2 Head TraumaConstant R 0.75% No Relief⁶ Resulting From Headache for 2 cc Drops AutoAccident circa 28 years P#3 Meningitis Monthly Headaches R 0.75%Transient Improvement⁶ circa 26 years of circa 3 2 cc Dropspre-treatment day duration P#4 Post Partum Migraine R 0.75% Initialpain: 9 Headaches 2 cc Drops Pain 3 min post-treatment: 0 No rebound upto 24 hours P#5 Posterior and Nausea R 0.75% Initial pain: 9 LateralPhotophobia 2 cc Drops Pain 15 min post-treatment: 0 Migraine No reboundup to 24 hours P#6 Post Partum Temporal and R 0.75% Initial pain: 8Headache Frontal Sat'd Cotton Pain 5 min post-treatment: 0 Headache SwabNo rebound up to 24 hours P#7 Temporal and Visual Changes R 0.75%Initial pain: 10 Frontal Sat'd Cotton Pain 2 min post-treatment: 0Headache of 2-3 Swab No rebound up to 24 hours or up Day Duration to 48hours P#8 Patient's First Loss of Vision R 0.75% Initial pain: 10Vascular Bed-ridden Sat'd Cotton Pain 10 min post-treatment: 0 HeadacheSwab Pain 24 hours post-treatment: 1 Episode (this pain was relieved by(CT scan ruled administering a 325 milligram out Tylenol ™ (McNeil-PPC,Inc., subarachnoid Fort Washington, PA) tablet) hemorrhage) No reboundup to two weeks P#9 Migraine R 0.75% Initial pain: 8.5 Sat'd Cotton Pain5 min post-treatment: 1 Swab No rebound up to 3 days P#10 MigraineNausea R 0.75% Initial pain: 9 Photophobia Sat'd Cotton Pain 3 minpost-treatment: 0 Swab No rebound up to one week P#11 Occipital Must liedown R 0.75% Initial pain: 9 Headache few 2 cc Drops Pain 15 minpost-treatment: 5 times per year Pain 60 min post-treatment: 0 Norebound up to one week P#12 Migraine L 2.0% Initial pain: 7 1 cc DropsPain 5 min post-treatment: 2 Pain 45 min post-treatment: 6^(B) P#13Marfan's Migraine Mild Nausea R 0.75% Initial pain: 6 Syndrome 2 SpraysPain 30 min post-treatment: 0⁶ No rebound up to 24 hours P#14 MigraineNausea R 0.75% Initial pain: 8 (Worst during Photophobia Sat'd CottonPain 3 min post-treatment: 0 menses) Visual changes Swab Pain 5 minpost-treatment: 2 Pain 18 hrs post-treatment: 8 (After 18 hrs, treatedw/spray) Retreated with 2 Pain following spray: 0⁶ Sprays No rebound upto 48 hours P#15 Viral Gastro- Sinus Headache Vertigo L 2.0% Initialpain: 6 intestinal developed after 1 cc Drops Pain 15 minpost-treatment: 0 Disturbance sneeze Pain 30 min post-treatment: 6 P#16Post Partum Post Dural L 2.0% Initial pain: 8 Headache Puncture 1 ccDrops Pain 15 min post-treatment: 4⁶ Headache P#17 Migraine Nausea R0.75% Initial pain: 8 Photophobia 2 Sprays Pain 15 min post-treatment: 2Pain 20 min post-treatment: 0⁶ No rebound up to 48 hours P#18 MigraineVisual changes R 0.75% Initial pain: 9 Sat'd Cotton Pain 3 minpost-treatment: 0 Swab P#19 Lumbar Disc Migraine R 0.75% Initial pain: 9Surgery Sat'd Cotton Pain 1 min post-treatment: 0 Swab No rebound up to48 hours P#20 Congenital Migraine Nausea R 0.75% Initial pain: 8Megacolon Vomiting Sat'd Cotton Pain 3 min post-treatment: 0 Swab Norebound up to one week P#21 Migraine Nausea R 0.75% Initial pain: 10Sat'd Cotton Pain 3 min post-treatment: 1 Swab Pain 5 minpost-treatment: 0 No rebound up to one week P#22 Cervical and R 0.75%Initial pain: 8 Occipital Sat'd Cotton Pain 10 min post-treatment: 0Headache Swab No rebound up to 24 hours P#23 Cervical Spine Cervical andNausea R 0.75% Initial pain: 9 Pain Occipital Sat'd Cotton Pain 5 minpost-treatment: 1 Headache Swab No rebound up to 24 hours P#24 MigraineR 0.75% Initial pain: 9 Sat'd Cotton Pain 3 min post-treatment: 0 SwabP#25 Recurrent Nausea R 0.75% Initial pain: 10 Parietal and Visualchanges Sat'd Cotton Pain 3 min post-treatment: 0 Occipital Swab Norebound up to one week Headaches, Bilateral Temporal Headaches P#26Migraine Nausea R 0.75% Initial pain: 10 Photophobia Sat'd Cotton Pain 5min post-treatment: 0 Swab No rebound up to 24 hours P#27 RecurrentNausea R 0.75% Initial pain: 10 Frontal, Photophobia Sat'd Cotton Pain 8min post-treatment: 0 Parietal, Swab No rebound up to 48 hours Temporal,and Occipital Headaches P#28 Migraine Nausea R 0.75% Initial pain: 9Visual changes Sat'd Cotton Pain 5 min post-treatment: 0 Swab No reboundup to 48 hours P#29 Migraine Nausea R 0.75% Initial pain: 10 PhotophobiaSat'd Cotton Pain 5 min post-treatment: 0 Swab No rebound up to 24 hoursP#30 Temporal Migraine Nausea R 0.75% Initial pain: 9 Arteritis, Sat'dCotton Pain 10 min post-treatment: 1 Steroid Use Swab No rebound up to18 hours P#31 Migraine R 0.75% Initial pain: 9 Sat'd Cotton Pain 2 minpost-treatment: 1 Swab No rebound up to 24 hours P#32 ChemotherapyMigraine Nausea R 0.75% Initial pain: 10 Sat'd Cotton Pain 15 minpost-treatment: 0 Swab P#33 Hypertension, Migraine Nausea, R 0.75%Initial pain: 9 Controlled Photophobia, 2 Metered Pain 5 minpost-treatment: 5 Diet Visual changes Sprays Pain 30 min post-treatment:3 Pain 90 min post-treatment: 0 (Patient presented one week later)Migraine 2 Metered Initial pain: 10 Sprays Pain 15 min post-treatment: 5Pain 30 min post-treatment: 4 Pain 90 min post-treatment: 0 No reboundup to one week P#34 Major Migraine Nausea, R 0.75% Initial pain: 7Depression, Photophobia 2 Metered Pain 20 min post-treatment: 3 ChronicSprays (Then repeated treatment using Hepatitis C two metered sprays) 2Metered Pain 5 min post-treatment: 0 Sprays (Patient presented sevenhours later) 2 Metered Initial pain: 2 Sprays Pain 10 minpost-treatment: 0 No rebound up to 24 hours P#35 Head Trauma MigraineNausea, R 0.75% Initial pain: 8 Visual changes 2 Metered Pain 30 minpost-treatment: 6 Sprays Pain 60 min post-treatment: 2 P#36 Complaintsof Migraine Nausea, R 0.75% Initial pain: 9 “Stuffy Nose” Photophobia, 2Metered Pain 5 min post-treatment: 7 Visual changes Sprays Pain 30 minpost-treatment: 5 P#37 Atypical Right Nausea, R 0.75% Initial pain: 7Side Headache Photophobia, 2 Metered Pain 30 min post-treatment: 3Behind Eye Intense Eye Sprays Pain 45 min post-treatment: 0 Pain &Pressure (Patient presented three days later) 2 Metered Initial pain: 2Sprays Pain 10 min post-treatment: 0 No rebound up to 48 hours P#38 HeadTrauma Migraine R 0.75% Initial pain: 3 2 Metered Pain 30 minpost-treatment: 0 Sprays P#39 Migraine Nausea R 0.75% Initial pain: 9 2Sprays Pain 2 min post-treatment: 0 No rebound up to 48 hours P#40Migraine Mild Nausea R 0.75% Initial pain: 10 Sat'd Cotton Patientexhibited apparent Swab allergic reaction between 5 and 15 minutespost-treatment Pain 20 min post-treatment: 3 Pain 30 min post-treatment:5 Level 5 pain endured 8 hours P#41 Head Trauma Recurrent Nausea, R0.75% Initial pain: 8 Headaches Photophobia, Sat'd Cotton Pain 20 minpost-treatment: 0 Perceived Swab No rebound up to 48 hours ‘WhistlingSounds’ P#42 Migraine Perceived R 0.75% Initial pain: 9 ‘FlashingLights’ Sat'd Cotton Pain 2 min post-treatment: 0 Swab No rebound up toone week Notes: ¹“Medical History” refers to events in the patient'smedical history deemed potentially related to the patient's headachesymptoms. ²“Headache History” describes the headache for which treatmentwas sought by the patient. ³“Associated Symptoms” describes symptomsdescribed by the patient as accompanying the headache for whichtreatment was sought, past recurrent headache episodes, or both.⁴Treatment” indicates the compound which was administered to thepatient: “R” refers to ropivacaine; “L” refers to lidocaine; # % refersto the concentration of the solution comprising the compound (expressedas % w/v); “2 Sprays” refers to delivery of less than about 0.5milliliter of the indicated solution delivered by two sprays into eachnostril of the patient using a sterile squeeze bottle containing thesolution; “# cc Drops” refers to delivery of # milliliters of theindicated solution via the modified nasal drip method described herein;“Sat'd Cotton Swab” refers to delivery of the indicated solution using astandard cotton swab saturated with the indicated solution as describedherein; “2 Metered Sprays” refers to delivery of less than about 0.5milliliter of the indicated solution delivered by a combination of twosprays into each nostril of the patient using a sterile metered-dosespray bottle containing the solution. ⁵“Results” refers to pain reliefexperienced by each patient, using the pain rating method of theInternational Headache Society (i.e., 10 = worst pain imaginable; 0 = nopain). The term “min” means minutes. ⁶This patient experiencedoropharyngeal numbness.

TABLE 2 Demographic and Pretreatment Characteristics of Patients.Characteristic Value Mean Age (Standard Error; Range) 45.1 years (±2.1years; 22-67) Gender Male   17 (45.9%) Female   20 (54.1%) Duration ofCurrent Headache, hours 23.2 (±4.1) (Standard Error) Mean Pain Level on10-Point Scale 8.64 (±0.223; 8.18-9.09) (Standard Error; 95% conf.interval) Patients Experiencing Nausea   23 (62.1%) PatientsExperiencing Photophobia   14 (37.8%)

Thirty-four of the thirty-seven (92%) migraine patients treated withropivacaine experienced significant (i.e., certainly greater than 50%)reduction of migraine severity. Complete relief followed ropivacaineadministration in 72% of the patients. Photophobia, nausea, and painwere simultaneously eliminated in migraine patients who experienced eachof these symptoms. Rebound was evident in only two of the respondingpatients, meaning that the rebound rate was only 5.4%. Adverse effectsof ropivacaine administration were minimal: one patient experienced anallergic response to ropivacaine administration, which responseconsisted of short-lived tachycardia, dizziness, and wheezing, all ofwhich endured for about twenty minutes before subsiding. Even thispatient who experienced an allergic response experienced a measurablereduction of migraine pain within twenty-five minutes post-treatment.

Pain Relief Effected by Cotton-Swab-Application of Ropivacaine

Among the twenty-four patients to whom ropivacaine was dorsonasallyadministered using a cotton swab, the mean pain severity rating prior toadministration of ropivacaine was 9.06±0.16 points out of a possible 10points (mean±standard error). The mean post-administration pain severityrating at the time of peak effect was 0.33±0.14 points out of a possible10 points. Thus, dorsonasal administration of ropivacaine using a cottonswab resulted in a mean peak headache severity rating reduction of8.73±0.249 points. The mean time that elapsed between the time oftreatment and the perception by the patient of the peak effect was7.41±1.47 minutes. Every patient in this group responded to treatment,95% of the patients achieving a pain severity rating of zero or one, and72% of patients achieving a pain severity rating of zero. One patient inthis group experienced rebound of headache pain eighteen hourspost-treatment. Thus, dorsonasal administration of ropivacaine using acotton swab causes significant pain reduction in 100% of migrainepatients, with rebound occurring in only 4% of patients.

Pain Relief Effected by Nasal-Drip-Application of Ropivacaine

Dorsonasal administration of ropivacaine effected by delivery of nasaldrops resulted in a mean peak headache severity rating reduction of 9.00points out of a possible 10 points in the three patients so treated. Themean time that elapsed between the time of treatment and the perceptionby the patient of the peak effect was 26.00±17.37 minutes. None of thethree patients experienced migraine rebound.

Pain Relief Effected by Nasal-Spray-Application of Ropivacaine

Dorsonasal administration of ropivacaine effected by delivery using thenasal spray method resulted in a mean peak headache severity ratingreduction of 6.22±0.66 points out of a possible 10 points in the tenpatients so treated. The mean time that elapsed between the time oftreatment and the perception by the patient of the peak effect was33.9±8.48 minutes. Of the ten migraine patients treated by intranasalspray, all experienced significant reduction in headache pain severity.The majority of these patients experienced complete headache pain reliefand did not experience rebound. The remainder experienced a meanheadache pain severity rating reduction of 87.5±6.49%. One of the tenpatients to whom ropivacaine was administered using a spray bottleexperienced a separate episode of migraine one week later.

Comparison of Administration of Ropivacaine by Cotton Swab, by NasalDrops, and by Nasal Spray

The results obtained in patients who were administered ropivacaine bythe three methods described herein are summarized in Tables 3 and 4.

TABLE 3 Effect of the Route of Ropivacaine Administration on Severity ofMigraine Pain. Pain Ratings and Pain Relief are measured using a10-point pain scale, as described herein. Pain Rating Prior Pain RatingAfter Method of Delivery to Administration Administration Pain ReliefCotton Swab 9.06 0.33 8.73 Nasal Drops 9.00 0.00 9.00 Nasal Spray 7.221.00 6.22

TABLE 4 Effect of the Route of Ropivacaine Administration on Severity ofMigraine Pain. Mean Mean Time Rate of Pain Number Reduction in UntilRelief (IHS of Pain Rating Maximal points per Method of DeliveryPatients (IHS points) Effect minute) Cotton Swab 24 8.64 7.41 2.32(Standard Error) (±0.25)   (±1.46) 95% confid. interval 8.12-9.164.37-10.4 Nasal Drops 3 9.00 26.0 1.25 (Standard Error) (0)   (±12.3)95% confid. interval 5.89-10.6  0-100 Nasal Spray 10 6.22 33.9 0.287(Standard Error) (±0.66)   (±8.48) 95% confid. interval 4.69-7.7514.31-53.46Comparison of the Therapeutic Effect of Dorsonasally-AdministeredRopivacaine and the Therapeutic Effect of Intranasally-AdministeredLidocaine

The anesthetic effect of 0.75% (w/v) ropivacaine-HCl is approximatelyequivalent to that of 3% (w/v) lidocaine. Intranasal sprayadministration of 1-2 milliliters of a 4% (w/v) lidocaine solution was55% effective to reduce pain associated with migraine (Maizels et al.,1996, J. Amer. Med. Assoc. 276:319-321). By comparison, as describedherein, dorsonasal spray administration of a 0.75% (w/v) ropivacainesolution was 100% effective to reduce pain associated with migraine.Furthermore, when dorsonasal administration of the ropivacaine solutionwas effected by topical application using a cotton swab saturated withthe solution, reduction of migraine pain was achieved in 100% ofpatients. Preliminary data indicate that bupivacaine exhibits efficacysimilar to that of ropivacaine for the relief of headache painassociated with migraine.

A comparison of ropivacaine and lidocaine on the basis of migraine painrelief per unit weight is provided in Table 5. This comparison indicatesthat dorsonasally spray-administered ropivacaine is 2.4 times as potentas intranasally spray-administered lidocaine, and that dorsonasallyswab-administered ropivacaine is more than 15 times as potent asintranasally spray-administered lidocaine. Furthermore, as indicated inTable 5, the rate of migraine rebound is much lower following dorsonasaladministration of ropivacaine, whether administered by nasal spray or bycotton swab, than it is following intranasal administration oflidocaine. Thus, the data presented herein indicate that ropivacaine isa much more efficacious agent for migraine pain relief than is lidocaineand that treatment of migraine by dorsonasal ropivacaine administrationhas a significantly lower rebound rate than treatment by intranasaladministration of lidocaine.

TABLE 5 Comparison of the efficacy of migraine treatment by dorsonasalropivacaine administration and the efficacy by intranasal lidocaineadministration. “Rate” indicates the rate of migraine pain reduction perminute per gram of drug administered to the patient. Pain was ratedusing a 10-point pain scale, as described herein. Route of Rate of PainRelative Rebound Drug Administration Relief Efficacy¹ Rate LidocaineIntranasal Spray 10.0 1.00 42% Ropivacaine Dorsonasal Spray 24.5 2.4510% Ropivacaine Dorsonasal Swab 155 15.5 4% ¹Relative Efficacy means theRate of Pain Relief for the indicated drug administered by the indicateroute divided by the Rate of Pain Relief for intranasallyspray-administered lidocaine.Comparison of the Therapeutic Effect of Ropivacaine and the TherapeuticEffects of Other Anti-Migraine Pharmaceutically Active Agents

In FIG. 3, the data obtained from the procedures performed in thisExample are presented and compared with recently reported data obtainedfor administration of lidocaine to migraine patients (Maizels et al.,1996, J. Amer. Med. Assoc. 276:319-321) or administration of sumatriptanto migraine patients (The Subcutaneous Sumatriptan International StudyGroup, 1991, New Eng. J. Med. 325:316-321). Administration ofropivacaine resulted in an earlier onset of relief and a higher responserate than did administration of sumatriptan. Although the time of onsetof relief using ropivacaine was roughly equal to the time of onset ofrelief using lidocaine, administration of ropivacaine treatment resultedin a nearly two-fold greater response rate than did administration oflidocaine. The response rate obtained by administration of ropivacaineto migraine patients was greater than the response rate obtained byadministration of rizatriptan to such patients. In addition, the reboundrate following ropivacaine administration was lower than the reboundrate following rizatriptan administration (Kramer et al., 1997, Headache36:268-269). The rapid and non-relapsing effects attributable todorsonasal administration of ropivacaine are not observed followingadministration of lidocaine or a serotonin receptor agonist administeredby the same route (Mills et al., 1997, Ann. Pharmacother. 31:914-915;Moore et al., 1997, Cephalalgia 17:541-550; Kramer et al., 1997,Headache 36:268-269).

While not wishing to be bound by any particular theory of operation, itis believed that dorsonasally administered ropivacaine inhibitedmigraine by anesthetizing a DnNS such as the SPG. Ropivacaine is ideallysuited for anesthesia of a DnNS in general, and for migraine relief inparticular. Ropivacaine exhibits intermediate lipid solubility and anintermediate half life in vivo, properties that limit possible toxicity.Direct application of ropivacaine to the region of the nasal epitheliumoverlying the SPG reduces the likelihood of systemic distribution of thecompound, thereby limiting the likelihood of numerous side effects.Furthermore, direct application of ropivacaine to the region of thenasal epithelium overlying the SPG reduces the amount of ropivacainewhich must be administered in order to provide an effectiveconcentration at the SPG for relief of an acute migraine episode.Ropivacaine and other local anesthetics related to aminoacyl localanesthetics are known to selectively affect sensory neurons, relative tomotor neurons, representing another advantage of using ropivacaine inthe method of the invention. It is believed that direct administrationof ropivacaine to the region of the nasal epithelium overlying the SPG,or to the region of the nasal epithelium near that region, arrests thecascade of neurotransmitter and neuropeptide release and stimulationthat lead to neurogenic inflammation observed in the course of an acutemigraine episode.

The ropivacaine molecule has the following structure (V), wherein thecarbon atom indicated by the asterisk is a chiral center:

Cardiotoxicity is a side effect of administration of the R(dextro)enantiomer of ropivacaine, but this side effect is not exhibited by theS(levo) enantiomer (deJong, 1995, Reg. Anesth. 20:474-481). For thisreason, ropivacaine is prepared as a sterile solution containing onlythe S(levo) enantiomer. The bupivacaine molecule also comprises a chiralcenter, but currently commercially available bupivacaine preparationsinclude both the S and the R enantiomers.

Many of the patients described in this Example were observed for up toseven days, and 95% of those patients experienced no rebound during thisperiod. This result contrasts with the results obtained followingintranasal lidocaine administration. Of the 55% of patients whoexhibited relief following intranasal lidocaine administration, at least42% experienced rebound, usually within one hour post-treatment (Maizelset al., 1996, J. Amer. Med. Assoc. 276:319-321). Similarly,administration of either sumatriptan or rizatriptan resulted ininhibition of pain in 40-50% of patients within two hours posttreatment, and patients who were administered either of these compoundsfrequently experienced rebound (The Subcutaneous SumatriptanInternational Study Group, 1991, New Eng. J. Med. 325:316-321; Kramer etal., 1997, Headache 36:268-269).

EXAMPLE 2 Dorsonasal Administration of Bupivacaine for Inhibition ofAcute Migraine Episodes

The purpose of the experiments described in this Example was todetermine the efficacy of dorsonasal administration of bupivacaine forinhibition of acute migraine episodes. Bupivacaine was dorsonasallyadministered to individual patients experiencing head pain, othersymptoms, or both, believed to be associated with an acute migraineepisode. Patients assessed head pain prior to and after bupivacaineadministration.

Dorsonasally administered bupivacaine provided rapid arrest of migrainein all seven patients to whom it was administered within 10 minutes orless. Symptoms such as nausea, visual changes, and photophobiaassociated with acute migraine episodes in the patients were similarlyreduced. Six of the seven patients treated using bupivacaine experiencedno rebound of their migraine within twenty-four hours of treatment. Theother patient experienced a recurrence of head pain four hours followinga first administration of bupivacaine and another episode of head paineight hours following a second administration of bupivacaine. Theseresults demonstrate that dorsonasal administration of bupivacaine is anefficacious method of inhibiting an acute migraine episode.

The materials and methods used in the procedures performed in thisExample were substantially the same as the materials and methodsdescribed in Example 1, with the exception that the composition whichwas administered to the patients described in this example comprised a0.75% (w/v) solution of bupivacaine.

The results of treatment of each of the seven patients described in thisExample with bupivacaine are presented in Table 6. The organization ofand the abbreviations used in Table 6 are analogous to those used inTable 1, with the exception that “B” in the treatment column refers tobupivacaine. These results indicate that dorsonasal administration ofbupivacaine is effective to inhibit acute migraine episodes.

TABLE 6 Summary of Patient Data. Patient Medical Headache AssociatedIdentifier History History Symptoms Treatment Results P2#1 MigraineNausea B 0.75% Initial pain: 5 2 Sprays Pain 10 min post-treatment: 0 Norebound up to 24 hours P2#2 Migraine Nausea B 0.75% Initial pain: 7Photophobia Sat'd Cotton Pain 5 min post-treatment: 0 Swab No rebound upto 24 hours P2#3 Migraine Visual Changes and B 0.75% Initial pain: 10nausea as aura. 2 cc Drops Pain 5 min post-treatment: 1-2 Followed byhead Head pressure persisted pressure and severe No rebound up to 24hours head pain at right occipital to front areas P2#4 Sinus Migraine B0.75% Initial pain: 8 Surgery Triggered 2 Sprays Pain 5 minpost-treatment: 0 by Recurrence 4 hours post-treatmt. Chocolate Pain 5min post-2nd-treatment: 0 Ingestion Recurrence 8 hours post-treatmt.P2#5 Mixed Nausea B 0.75% Initial pain: 8 Headache Photophobia 2 SpraysPain 10 min post-treatment: 0 No rebound up to 24 hours P2#6 Migraine B0.75% Initial pain: 8 2 Sprays Pain 3 min post-treatment: 0 No reboundup to 24 hours P2#7 Migraine Visual Changes B 0.75% Initial pain: 10 2cc Drops Pain 10 min post-treatment: 0 No rebound up to 24 hours

EXAMPLE 3 Inhibiting a Recurring Cerebral Neurovascular Disorder byDorsonasally Administering a Long-Acting Local Anesthetic Decreases theFrequency and Severity of Subsequent Episodes

The following studies relate to the methods of decreasing the frequencyand severity of CNvD episodes described herein, and involved threepatients.

A 25-year-old female patient, herein designated “patient 3-1” wasafflicted with recurring severe migraine, wherein acute migraineepisodes were associated with nausea and visual changes. Patient 3-1generally rated the severity of head pain associated with acute migraineepisodes in the range from five to eight using the pain scale describedherein. Patient 3-1 experienced, on average, about one acute migraineepisode per week prior to beginning dorsonasal ropivacaine therapy. Inaddition, patient 3-1 also usually experienced about one severe acutemigraine episode per month, associated with menses, wherein the severityof head pain was from eight to ten using the pain scale describedherein. Patient 3-1 did not respond satisfactorily to administration ofbeta blockers and sumatriptan.

Ropivacaine was dorsonasally administered to patient 3-1 using thecotton swab technique described herein. The patient has consistentlyexperienced relief from all of the symptoms of her CNvD episodes within3 to 5 minutes following administration of ropivacaine, regardless ofwhether the episodes are associated with menses.

Patient 3-1 has continued treatment according to this method for aboutsix months. After beginning the ropivacaine treatment, the patientdiscontinued use of sumatriptan and propanolol. Discontinuing thesemedications did not result in a loss of efficacy attributable toropivacaine administration. Starting about three or four monthsfollowing initiation of ropivacaine administration, the patient noticeda decrease in the initial severity of acute migraine episodes notassociated with menses. At about the same time, the patient furthernoticed a decrease in the frequency with which acute migraine episodesnot associated with menses occurred. No decrease in either the initialseverity or the frequency of acute migraine episodes associated withmenses has been reported by the patient. Patient 3-1 continues toexperience relief from the head pain and other symptoms of acutemigraine episodes, including those associated with menses, uponadministration of ropivacaine.

A 45-year-old male, herein designated, “patient 3-2,” was afflicted withrecurring migraines. The acute migraine episodes began when he was ateenager, and have significantly worsened over the past 15 years. Headpain associated with the patient's acute migraine episodes is typicallypreceded by visual changes which he describes as a curtain-like wave ofscotomata moving from left to right until he is unable to see. Thepatient then becomes disoriented with respect to time and place and mustsit or lay down. Following these prodromal symptoms, a severe headache,rated 10 on the pain scale described herein, begins and typicallyendures for 45 to 60 minutes. The patient remains completely debilitatedfor the duration of the headache, unable to move about or walk. As theheadache subsides, the patient's vision returns, and the patient is leftfeeling exhausted, as if he had not slept the night before.

Following dorsonasal administration of ropivacaine, delivered by thenasal spray method described herein, patient 3-2 noticed an abrupt haltto the progression of visual changes and steady resolution of his visualdeficit. The headache rapidly decreased in intensity, decreasing from apain intensity of 10, using the pain scale described herein, to anintensity of 2-3 within one to two minutes. The headache was completelyresolved by fifteen minutes following ropivacaine administration. Thispatient also noted that he did not feel exhausted following the treatedacute migraine episode. After four to six months of dorsonasalropivacaine therapy, the patient noted that his headaches occurred lessfrequently, at a rate of approximately one headache every two months orlonger. Furthermore, the severity of the headaches that patient 3-2experienced was significantly reduced following this course of therapy.Prior to the course of dorsonasal ropivacaine therapy, the patient'sheadaches ordinarily had a pain intensity of about 10; after four to sixmonths of this therapy, the initial headache pain (i.e., even prior toropivacaine administration) was not greater than about 2. The patientreports significant lifestyle improvement, and is not aware of any otherchanges, for example changes in diet, sleep, exercise, environment, ormedication, that could account for this improvement.

A 40-year-old female, herein designated, “patient 3-3,” experiencedabout 3 to 5 recurring migraine episodes per week prior to beginningdorsonasal ropivacaine therapy. The initial severity of these headacheswas reported to be 10, using the pain scale described herein. Whenropivacaine was administered, using the saturated swab method describedherein, to patient 3-3 during a headache episode, the patient reported adecrease in head pain from a rating of 10 to a rating of 0 or 1 within10 minutes following ropivacaine administration. Furthermore, afterthree months of dorsonasal ropivacaine treatment, patient 3-3 reportedthat the frequency of her headache episodes had decreased to about 1 to2 times weekly and that the initial severity of her headaches was in therange from about 7 to about 8, rather than 10.

The data described in this Example indicate that dorsonasaladministration of ropivacaine to a patient afflicted with a recurringCNvD both inhibits a single episode of the CNvD and decreases thefrequency and initial severity of the episodes associated with therecurring CNvD. Thus, the compositions, kits, and methods of theinvention are useful for decreasing the frequency with which a patientafflicted with a recurring CNvD experiences a CNvD episode and forotherwise inhibiting the CNvD.

EXAMPLE 4 Inhibition of Tinnitus by Dorsonasal Administration ofRopivacaine

The data presented in this example demonstrate that symptoms of tinnitusmay be inhibited by dorsonasal administration of a local anesthetic.Ropivacaine was dorsonasally administered to each of three patientsusing the nasal spray method or the nasal drops method described herein.All three patients experienced inhibition of tinnitus.

The first patient, herein designated, “patient 4-1,” was a healthy malepatient in his thirties who was afflicted with occasional migrainescomplicated by bilateral tinnitus about once every two to three months.Dorsonasal spray administration of ropivacaine to patient 4-1 relievedthe head pain and tinnitus symptoms experienced by this patient withinabout five minutes following administration.

The second patient, herein designated, “patient 4-2,” was a male in hisforties who was afflicted with chronic head, neck, back, and shoulderpain resulting from trauma sustained during multiple motor vehicleaccidents. Patient 4-2 was afflicted with constant head pain for whichhe used large quantities of intranasally-administered butorphanol. Itwas believed that the patient's headaches did not have a neurovascularetiology. Patient 4-2 is also afflicted with continuous bilateraltinnitus. Following dorsonasal spray administration of ropivacaine topatient 4-2, the patient reported a decrease in head pain of about 2points, using the pain scale described herein, and furthermoreexperienced complete relief from symptoms of tinnitus for a period of 30to 45 minutes. Interestingly, this patient noted a faster onset and afar more powerful effect on his chronic non-headache pain ofintranasally administered butorphanol following intranasaladministration of ropivacaine.

The third patient, herein designated, “patient 4-3,” was a healthy malein his sixties who was afflicted with bilateral tinnitus for over 30years. Following dorsonasal administration of 1 milliliter of 0.75%(w/v) ropivacaine into each nostril by the nasal drop method describedherein, patient 4-3 experienced complete relief from tinnitus symptomsin his left ear and a 50-75% reduction in tinnitus symptoms in his rightear. This patient's relief from and reduction of symptoms persisted forabout 30 to 45 minutes, after which period the tinnitus symptomsreturned.

The results of the experiments described in this Example indicate thatdorsonasal administration of a local anesthetic inhibits tinnitus. Eventhough the relief of tinnitus in these three patients was relativelyshort-lived (relative to migraine relief, as described herein), it mustbe borne in mind that no effective treatment exists for tinnitus. Thus,the treatment method described herein for tinnitus can be used toprovide at least temporary relief to patients who have no effectivelong-term treatment options. Furthermore, the results presented in thisExample suggest that a sustained release preparation of a localanesthetic or a local anesthetic causing a longer duration of anesthesiathan ropivacaine may provide a longer period of inhibition of tinnitusthan the ropivacaine preparation used in this method.

EXAMPLE 5 Dorsonasal Administration of Bupivacaine for Treatment ofMuscular Headache Episodes

The purpose of the experiments described in this Example was todetermine the efficacy of dorsonasal administration of bupivacaine forinhibition of muscular headaches. Bupivacaine was dorsonasallyadministered to four individual patients experiencing head pain andother symptoms associated with a severe muscular headache episode. Allof the patients had areas of sustained craniocervical muscle contractionand tenderness which was absent in all patients following headacheresolution. Patients assessed head pain prior to and after bupivacaineadministration. The four patients and their responses were as follows.

Patient 1

This patient was a 68-year-old female who experienced classic tensionheadache symptoms under stress. The patient normally experienced reliefof tension headache symptoms following administration of ibuprofen. Thepatient was administered 0.75% bupivacaine during a tension headacheepisode, and thereafter experienced relief of her headache symptoms. Thepatient's pain intensity, as assessed using the pain scale describedherein, decreased from about 8 to 0 within about 15 minutes afterbupivacaine administration.

Patient 2

This patient was a 38-year-old male who experienced typical musclecontraction headache symptoms. The patient normally experienced reliefof headache symptoms following administration of acetaminophen. Thepatient was administered 0.75% bupivacaine during a muscle contractionheadache episode, and thereafter experienced relief of his headachesymptoms within seven minutes following bupivacaine administration. Thepatient's pain intensity, as assessed using the pain scale describedherein, decreased from about 7 to 0 within about 7 minutes afterbupivacaine administration.

Patient 3

This patient was a 25-year-old male who experienced cervical neck painsymptoms associated with tension headache. The patient experiencedmoderate relief of headache symptoms following administration ofnon-steroidal anti-inflammatory drugs, including ibuprofen. The patientwas administered 0.75% bupivacaine during a tension headache episode,and thereafter experienced relief of his headache symptoms. Thepatient's pain intensity, as assessed using the pain scale describedherein, decreased from about 5 to about 1 within about 5 minutes afterbupivacaine administration.

Patient 4

This patient was a 44-year-old female who experienced tension headaches.The patient was administered 0.75% bupivacaine during a tension headacheepisode, and thereafter experienced relief of neck pain and bi-temporaltension headache pain symptoms. The patient's pain intensity, asassessed using the pain scale described herein, decreased from about 7to about 1 within about 5 minutes after bupivacaine administration.Prior to bupivacaine administration, the patient experienced mildresidual pain in response to deep palpation of affected neck and templemuscles. This pain was perceived to be markedly decreased followingtreatment, and muscle knots were no longer perceived 5 minutes aftertreatment.

It is recognized that the muscular headache inhibition described in thisExample may have been secondary to neurovascular effects of adorsonasally administered local anesthetic or to effects on one or bothof intracranial or extracranial neural or vascular structures, asdescribed herein.

EXAMPLE 6 Dorsonasal Administration of a Eutectic Mixture of LocalAnesthetics

An amount (0.5-1.0 milliliters) of a commercially available eutecticmixture of local anesthetics (prilocalne/lidocaine, 2.5% (w/v) each;EMLA™, Astra USA, Westborough, Mass.) was dorsonasally administered toeach of six healthy adults using a syringe having a flexible applicatorattached thereto. None of the six adults noted oropharyngeal numbness,unpleasant taste, or any other side effect normally associated withadministration of a local anesthetic following intranasaladministration.

The same amount of the mixture was dorsonasally administered to fivepatients afflicted with headaches. Each of these five patientsexperienced complete or nearly complete inhibition of head pain andother symptoms of their headaches within ten minutes followingadministration.

EXAMPLE 7 Dorsonasal Headache Treatment Using Lidocaine

Three headache patients were treated by delivering about 20-50milligrams of a 10% (w/v) lidocaine solution to each nostril of thepatients. The solution was administered by spraying it through a plasticcannula which had been bent to conform its shape such that the outlet ofthe cannula was located dorsonasally. The cannula was inserted into eachnostril, and the solution was sprayed through the cannula, exitingtherefrom through the outlet. All three patients experienced rapidrelief from their headache symptoms; however, headache symptomsrebounded in two of the patients in less than one hour.

EXAMPLE 8 Dorsonasal Headache Treatment Using Bupivacaine

Two different headache patients were treated by delivering about0.25-0.75 milliliters of a 0.75% (w/v) bupivacaine solution to eachnostril of the patients. The solution was administered by passing thesolution along a plastic cannula having an absorbent portion affixed atthe distal (i.e., outlet) portion thereof. This cannula had also beenbent to conform its shape such that the outlet of the cannula and theaffixed absorbent portion were located dorsonasally. The solution waspassed along the cannula, and the cannula was left in place for severalminutes. Both of these patients experienced rapid relief from theirheadache symptoms, and neither patient experienced rebound of headachesymptoms within about one day, the end of the follow-up period for thesepatients.

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety.

While this invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention. The appendedclaims are intended to be construed to include all such embodiments andequivalent variations.

1. A method of inhibiting a cerebral neurovascular disorder associatedwith pain in a human patient, the method comprising implanting anelectronic neural stimulator in patient tissue adjacent a dorsonasalnerve structure and energizing the implanted electronic neuralstimulator, so as to inhibit pain.
 2. The method of claim 1 wherein thedorsonasal nerve structure is an SPG or branch thereof.
 3. The method ofclaim 1 further comprising providing power to the implanted electronicneural stimulator using an external power supply.
 4. The method of claim3 wherein the step of providing power comprises inductively coupling theexternal power supply to the electronic neural stimulator.
 5. The methodof claim 1 further comprising effecting nerve block of the dorsonasalnerve structure.
 6. A method of inhibiting migraine or headache in ahuman patient, the method comprising implanting an electronic neuralstimulator in patient tissue adjacent a dorsonasal nerve structure andenergizing the implanted electronic neural stimulator to effect nerveblock of the dorsonasal nerve structure, so as to inhibit the migraineor the headache.
 7. The method of claim 6 wherein the dorsonasal nervestructure is an SPG or branch thereof.
 8. The method of claim 6 furthercomprising providing power to the implanted electronic neural stimulatorusing an external power supply.
 9. The method of claim 8 wherein thestep of providing power comprises inductively coupling the externalpower supply to the electronic neural stimulator.